A SELF-TEST IM BOARD REVIEW JAMES K. STOLLER, MD, EDITOR ON A CLINICAL EMIL HAYEK, MD Assistant professor of Medicine, Northeastern Ohio CASE Universities College of Medicine, Rootstown, OH; cardiologist, Akron General Medical Center, Akron, OH

An elderly woman with severe anemia

77-YEAR-OLD WOMAN IS ADMITTED to ■ DIFFERENTIAL DIAGNOSIS A the hospital with complaints of severe generalized weakness and dizziness. She denies Which is the most likely cause of her anemia? having abdominal pain, rectal bleeding, mele- 1 na, or hematemesis. ❑ Anemia of chronic disease Her medical history includes hypertension, ❑ Iron-deficiency anemia hypothyroidism, total abdominal hysterectomy, ❑ Myelodysplastic syndrome and cholecystectomy. Her current medications ❑ Beta-thalassemia include triamterene and hydrochlorothiazide (Dyazide, Maxzide), conjugated estrogen (Pre- Iron deficiency is the most common cause of a marin), levothyroxine (Synthroid), and alen- microcytic anemia in postmenopausal women. dronate (Fosamax). Anemia of chronic disease (eg, in chron- She looks pale but otherwise seems well. ic inflammation, infection, and malignancy) She is afebrile, and her blood pressure is can cause hypochromic, microcytic anemia 154/83 mm Hg without orthostatic change, due to iron-deficient erythropoiesis; however, pulse 82 per minute, and oxygen saturation this anemia usually is normochromic and nor- 100% on room air. mocytic. Her peripheral The physical examination is normal, no Patients with myelodysplastic syndromes, blood smear masses are palpable on rectal examination, which encompass a heterogeneous group of and her stool is guaiac-negative. clonal disorders of myeloid hematopoiesis, shows Routine laboratory studies are performed may present with anemia, but this is usually hypochromic, (TABLE 1). A peripheral blood smear shows macrocytic and is often accompanied by other microcytic hypochromic, microcytic erythrocytes. cytopenias. erythrocytes T ABLE 1 The patient’s laboratory study results

TEST PATIENT’S VALUES NORMAL RANGE

White blood cell count 5.0 × 109/L 4.4–9.7 Hemoglobin concentration 7.7 g/dL 11.7–14.7 Hematocrit 28.3% 34.7–43.3 Mean corpuscular volume 62 fL 82–97 Red cell distribution width 21% 12–15 Platelet count 345 × 109/L 150–370 Sodium 143 mmol/L 136–145 Potassium 3.6 mmol/L 3.5–5.3 Chloride 105 mmol/L 100–111 Blood urea nitrogen concentration 18 mg/dL 3–25 Serum creatinine concentration 1.3 mg/dL 0.7–1.5 Thyrotropin 3.84 µIU/L 0.4–4.5

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Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. Beta-thalassemia trait, an inherited het- The most common cause of iron-deficiency erozygous defect in beta-globin chain synthe- anemia in a postmenopausal woman without sis, also causes microcytic anemia; however, it an obvious source of blood loss is occult gas- would be unusual for this diagnosis to be made trointestinal bleeding. The differential diag- initially in a 77-year-old woman. nosis includes colorectal carcinoma, peptic ulcer disease, inflammatory bowel disease, and ■ CONFIRMING IRON DEFICIENCY vascular ectasia. While iron deficiency is the most common nutritional deficiency world- Acting on the presumed diagnosis of iron-defi- wide, there is nothing in our patient’s history ciency anemia, her physicians measure her to suggest inadequate nutritional intake or serum ferritin concentration, which is 4 ng/mL impaired iron absorption, such as may occur (normal postmenopausal range 18–300). It with atrophic gastritis. Colonoscopy and EGD should be noted that, due to age-specific varia- offer the highest probability of detecting the tion in serum ferritin levels in normal individu- source of occult gastrointestinal bleeding, and als, the diagnostic sensitivity for iron-deficien- they should be the first tests performed.3 cy in the elderly is improved by using a higher Capsule endoscopy, which is performed by cutoff of 45 to 60 ng/mL. having the patient swallow a wireless, pill-sized video camera, is used to investigate the small Which study is required to confirm iron- bowel, which cannot be visualized by EGD or 2 deficiency anemia? colonoscopy. Small-bowel sources of blood loss ❑ Bone marrow examination are less common, so capsule endoscopy should ❑ Serum iron be considered if colonoscopy and EGD do not ❑ Total iron-binding capacity reveal the cause of the blood loss. ❑ No further testing is necessary Tagged red blood cell radionuclide imag- ing is used to determine the site of active rapid The finding of a markedly reduced serum fer- bleeding exceeding 0.1 to 0.4 mL per minute. ritin concentration (< 10 ng/mL) confirms Air-contrast barium enema examination severe iron deficiency with a specificity of can identify mass lesions, but endoscopy is more Colonoscopy 99%, thus obviating the need for a confirmato- sensitive for detecting mucosal lesions or vascu- and EGD could ry bone marrow examination. Total iron-bind- lar ectasia and would therefore be preferred. ing capacity, an indirect measure of the serum not find the transferrin concentration, is usually elevated ■ ENDOSCOPIC STUDIES ARE NORMAL, source of her with iron deficiency but is a less specific find- NEW SYMPTOMS DEVELOP ing than a low serum ferritin. In the presence occult bleeding of both iron-deficiency anemia and anemia of The patient undergoes colonoscopy and EGD, chronic disease, serum iron is decreased; serum which are normal. Given our patient’s profound ferritin is normal to increased in anemia of symptoms of severe anemia and given her chronic disease.1 Therefore, the finding of advanced age, she receives a transfusion of packed microcytic anemia with severely reduced red blood cells and is started on oral ferrous sulfate. serum ferritin confirms the diagnosis of iron- One month later she develops palpitations, deficiency anemia, and no further testing is watery , and episodic facial . necessary.2 Which laboratory study should be ordered ■ FINDING THE SOURCE OF BLEEDING 4 next? ❑ 24-hour urine collection for Which test should be performed next in metanephrines and vanilmandelic acid 3 this patient? ❑ 24-hour urine collection for 5-hydroxy- ❑ Capsule endoscopy indoleacetic acid (5-HIAA) ❑ Tagged red blood cell radionuclide imaging ❑ Serum ❑ Colonoscopy and esophagogastroduode- ❑ Carbohydrate antigen 125 (CA-125) noscopy (EGD) ❑ Serum serotonin plus 24-hour urine ❑ Air-contrast barium enema x-ray collection for 5-HIAA

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TABLE 2 with hepatic metastases. Given the inherent difficulties of accurate 24-hour urine collec- Differential diagnosis tion and preservation, especially in the elder- of facial flushing ly, it is useful to concomitantly measure other Diseases biochemical markers in the blood. Elevated Autonomic epilepsy plasma, whole blood, and platelet serotonin syndrome and fasting plasma 5-HIAA are biomarkers Mastocytosis highly specific and modestly sensitive for car- Medullary thyroid carcinoma cinoid tumor, especially in patients with Migraine . More recently, plasma chromo- granin A has been found to be a sensitive bio- Polycythemia Renal cell carcinoma chemical marker for both diagnosis and mon- itoring of disease progression. Medications The studies in this patient showed Nicotinic acid markedly elevated urinary 5-HIAA (118.7 Phosphodiesterase-5 inhibitors mg/24 hours, normal < 6.0 mg/24 hours) and (sildenafil, tadalafil, vardenafil) serum serotonin (2,233 pmol/mL, normal < Foods 180 pmol/mL), confirming the diagnosis of Alcohol malignant carcinoid syndrome. Monosodium glutamate An important note: ingestion of amine- Sodium nitrite (cured meats) rich foods such as bananas may cause elevated Sulfites urinary 5-HIAA levels in the absence of car- Other cinoid tumor (ie, a false-positive result) and Anxiety should be avoided for at least 12 hours before Idiopathic measurement. Accordingly, our patient avoid- Menopause ed amine-rich foods for 12 hours before the urine collection. In carcinoid Urinary excretion of metanephrines and syndrome, vanilmandelic acid is elevated in patients The differential diagnosis of facial flushing is with pheochromocytoma, a rare tumor usual- serotonin broad and includes anxiety, medical condi- ly of adrenal origin that causes episodic palpi- causes flushing, tions such as mastocytosis, and the use of alco- tations, hypertension, headache, and sweating hol and various medications (TABLE 2).4–6 If the due to release of —an unlikely diarrhea, and flushing is due to foods, alcohol, or medica- diagnosis in our patient, who lacks this con- bronchospasm tions, a careful history will usually point to the stellation of symptoms. cause. Flushing reactions with alcohol are CA-125 is a tumor antigen associated more common in the Asian population due to with ovarian carcinoma. Ovarian carcinoma alcohol dehydrogenase deficiency, and it also would be highly unlikely in this patient, how- occurs with the concomitant use of drugs such ever, given her history of total abdominal hys- as disulfiram (Antabuse), chlorpropamide terectomy. (Diabinese), paroxetine (Paxil, Pexeva), and metronidazole (eg, Flagyl). The presence of ■ CARCINOID SYNDROME associated systemic symptoms, such as in our patient, should prompt a search for a more Carcinoid tumors are rare, with an incidence serious underlying condition, such as a neu- of 1 to 2 per 100,000 in the United States, but roendocrine tumor, eg, pheochromocytoma or are the most common .7 carcinoid tumor. They are most often found in the gastroin- The best next step in our patient is to testinal tract (74% of cases), particularly in measure the 24-hour urinary excretion of the the small bowel and appendix, but they are serotonin metabolite 5-HIAA. Elevated uri- also found in the bronchopulmonary system nary excretion of 5-HIAA is a specific marker (25% of cases).7 for carcinoid tumor, particularly in a patient Carcinoid tumors in the bowel can pre-

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Downloaded from www.ccjm.org on October 2, 2021. For personal use only. All other uses require permission. sent with iron-deficiency anemia, while gas- tric carcinoid may cause pernicious anemia.8 Carcinoid tumors may present with localized symptoms (eg, intestinal obstruction) or sys- temic symptoms (as in carcinoid syndrome), or they may be found incidentally during , endoscopy, or autopsy.

■ FINDING THE TUMORS Which is the best next step in the evalua- 5 tion of this patient? ❑ Exploratory laparotomy ❑ Contrast-enhanced abdominal computed FIGURE 1. Abdominal computed tomography with contrast shows numerous low-density tomography (CT) ❑ hepatic nodules (arrows) in both lobes due Radiolabeled receptor to metastatic carcinoid tumor. ❑ Hepatic venous sampling , a somatostatin analogue, offers excel- Our patient presented with carcinoid syn- lent sensitivity and is superior to scintigraphy drome, and hepatic metastases are likely on with meta-iodobenzylguanidine (MIBG) iodine the basis of her symptoms of flushing, diar- 131. However, while scintigraphy is an excellent rhea, and palpitations. choice for tumors that cannot be located by CT Carcinoid syndrome, characterized by or MRI, it is also technically more difficult to per- episodic flushing (usually of the face and form than CT and is not as accurate as CT at chest), secretory diarrhea, and bronchospasm, determining the size of the tumor and its proxim- occurs when high serum concentrations of ity to surrounding structures, and therefore it vasoactive substances released by the tumor, should not be the initial study. Carcinoid most notably serotonin, reach the systemic Hepatic venous sampling is an invasive syndrome can circulation. Most of the time this occurs when method and should be reserved for the rare and there is distant metastasis, usually to the liver. particularly challenging diagnosis of carcinoid indicate distant Polypeptide hormones, particularly those syndrome when the tumor is not visualized by metastases, responsible for production, are less invasive means such as CT or MRI. implicated in flushing symptoms and bron- eg, to the liver choconstriction, while increased intestinal Imaging results levels of tachykinins have been associated Abdominal CT in our patient reveals a 3-by- with secretory diarrhea. 2-cm mass at the root of the small-bowel Imaging studies such as CT, magnetic res- mesentery, as well as numerous low-density onance imaging (MRI), positron emission nodules consistent with metastases in both tomography, and radionuclide studies can hepatic lobes (FIGURE 1). Fine-needle aspiration determine the location and the stage of the of one of the hepatic masses shows monoto- tumor before surgical exploration. Contrast- nous sheets of cells that stain strongly for both enhanced abdominal CT would be the nonin- chromogranin and neuron-specific enolase, vasive study most likely to yield the diagnosis. products of neuroendocrine tumors (FIGURE 2). Exploratory laparotomy should not be the initial diagnostic test: a noninvasive imaging ■ WHAT ARE HER TREATMENT OPTIONS? test should be done first to locate the primary tumor and detect distant metastasis, thus Which treatment option should be consid- determining the appropriate medical and sur- 6 ered at this point? gical therapy. ❑ Surgical resection of the small bowel Since most carcinoid tumors express somato- tumor and the hepatic metastases statin receptors, scintigraphy with radiolabeled ❑ Chemoembolization of the hepatic artery

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FIGURE 2. Fine-needle aspiration of a hepatic mass shows monotonous round carcinoid cells (A) that stain strongly for chromogranin (B).

❑ Monthly injections of octreotide About 70% of carcinoid tumors have ❑ MIBG iodine 131 receptors for MIBG, a biogenic amine precur- ❑ All of the above except for surgical sor analogue that is taken up by neuroen- resection of the tumor and metastases docrine tumors. Targeted radiation therapy with MIBG iodine 131 in receptor-positive All of the above are options except for surgi- patients has been shown to relieve symp- cal resection. Surgical resection is an option toms.11 when metastatic disease is confined to a sin- gle hepatic lobe, particularly with a solitary ■ MORE SYMPTOMS DEVELOP tumor; however, most patients have unre- sectable disease at the time of diagnosis, and The patient is treated with octreotide but surgery, even when feasible, is rarely cura- develops refractory symptoms of flushing and With carcinoid tive. diarrhea with an associated increase in size of tumors, The goals of treatment in this patient the hepatic metastases. She undergoes hepat- should be cytoreduction and control of symp- ic artery chemoembolization of the largest octreotide toms that are due to excess circulating neu- hepatic tumor, which improves her symptoms. helps with ropeptides. Three months later she develops increas- By inhibiting neuropeptide release, ing dyspnea and lower-extremity edema. The symptoms somatostatin analogues such as octreotide, physical examination shows elevated jugular but does not usually given as a monthly injection, offer venous pressure with a prominent v wave, prolong symptomatic improvement in most patients.9 clear lung fields, loud pansystolic murmur However, octreotide has not been shown to along the lower left-sternal border accentuat- survival prolong survival or to have any impact on ed with inspiration, loud P2, severe bilateral hepatic tumor burden. leg edema, and ascites. Systemic is of limited value due to poor response rates and systemic Which is the most likely explanation for toxicity. 7 these symptoms? Hepatic tumor cytoreduction has been ❑ Thrombosis of the inferior vena cava achieved by surgical approaches such as intra- ❑ Carcinoid crisis operative cryoablation and radiofrequency ❑ Carcinoid heart disease ablation, as well as by catheter-based tech- ❑ Cardiac metastasis niques. Targeted therapy either with hepatic artery embolization or chemoembolization has The findings of our patient’s cardiac examina- been used successfully to diminish symptoms tion are consistent with severe tricuspid insuffi- and tumor burden in patients with unre- ciency and resultant right-sided , sectable disease.10 which is characteristic of carcinoid heart disease,

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A B

RV LV RV

RA LA

RA

FIGURE 3. Two-dimensional echocardiography (at end-diastole with closed mitral valve) shows marked retraction of the tricuspid leaflets and failure of coaptation (A, arrows). This resulted in severe tricuspid insufficiency, as seen on color Doppler imaging (B, arrow).

and which we confirmed in this patient with cardial fibrotic plaques, as evidenced by the two-dimensional echocardiography (FIGURE 3). correlation of urinary 5-HIAA levels and the Tumor extension into the inferior vena development of carcinoid heart disease.12 cava is most often associated with renal cell carcinoma. Carcinoid crisis is a rare, life-threat- How should this patient be managed? ening, acute complication of surgical resection 8 or chemotherapy characterized by hypotension, ❑ Diuretics to control symptoms profound flushing, confusion, and hyperther- ❑ Beta-antagonists mia. Most cardiac tumors are benign, and the ❑ Tricuspid valve replacement most common metastatic tumors to the heart ❑ Tricuspid valve annuloplasty Carcinoid are bronchogenic carcinoma, breast carcinoma, heart disease , and lymphoma. Loop diuretics along with salt and water restriction treat the symptoms of right-sided is usually ■ CARCINOID SYNDROME AND THE HEART heart failure and would be appropriate in our confined to patient. Beta-antagonists may worsen right- Cardiac involvement occurs in as many as sided heart failure in patients with right ven- the right heart 66% of patients with carcinoid syndrome and, tricular dysfunction. Tricuspid valve replace- as the tumor-released vasoactive substances ment, often with pulmonary valvuloplasty, are inactivated by the lung, primarily affects may be considered in some younger patients, the right heart. Left heart involvement is less particularly when carcinoid heart involve- frequent but may occur with patent foramen ment is diagnosed early, as the cause of death ovale, bronchopulmonary carcinoid, or very in these patients is more often right-sided high levels of circulating serotonin from heart failure rather than progressive malignan- extensive hepatic metastases. cy.13 Tricuspid valve replacement is preferred The most common finding is endocardial over annuloplasty repair due to marked retrac- fibrosis of the tricuspid and pulmonary valves tion of the valve leaflets. leading to tricuspid insufficiency, tricuspid The patient develops progressive right- stenosis, and pulmonic stenosis due to thick- sided heart failure and dies 2 years after the ening, retraction, and fixation of the leaflets diagnosis of carcinoid syndrome. (FIGURE 3). The degree of tricuspid insufficiency is usually much more severe than the degree of ■ TAKE-HOME POINTS stenosis and leads to dilation and dysfunction of the right ventricle. • Carcinoid tumors are rare neuroendocrine Serotonin appears to play a significant tumors usually localized to the gastroin- role in the development of the typical endo- testinal tract.

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• Carcinoid syndrome occurs with metasta- tic disease to the liver and results in symptoms of flushing, diarrhea, and bron- chospasm due to circulating serotonin and neuropeptides. •Most patients with carcinoid syndrome have unresectable disease, and manage- ment is confined to symptom relief and cytoreduction. • Carcinoid heart disease, usually confined to the right heart, is commonly seen with carcinoid syndrome and may lead to right-sided congestive heart failure.

■ REFERENCES

1. Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. Laboratory diagnosis of iron-deficiency anemia: an overview. J Gen Intern Med 1992; 7:145–153. 2. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352:1011–1023. 3. Rockey DC. Occult gastrointestinal bleeding. N Engl J Med 1999; 341:38–46. 4. Tur E, Ryatt KS, Maibach HI. Idiopathic recalcitrant facial flushing syndrome. Dermatologica 1990; 181:5–7. 5. Friedman BS, Germano P, Miletti J, Metcalfe DD. A clinicopathologic study of ten patients with recurrent unexplained flushing. J Allergy Clin Immunol 1994; 93(1 Pt 1):53–60. 6. Aldrich LB, Moattari AR, Vinik AI. Distinguishing fea- tures of idiopathic flushing and carcinoid syndrome. Arch Intern Med 1988; 148:2614–2618. 7. Modlin IM, Sandor A. An analysis of 8305 cases of car- cinoid tumors. Cancer 1997; 79:813–829. 8. Coppola A, Izzo G, Mastrolorenzo L, et al. A 69-year- old woman with persistent iron deficiency anemia. Ann Hematol 2004; 83:474–476. 9. Arnold R, Trautmann ME, Creutzfeldt W, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroen- teropancreatic tumours. Gut 1996; 38:430–438. 10. Gupta S, Johnson MM, Murthy R, et al. Hepatic arteri- al embolization and chemoembolization for the treat- ment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005; 104:1590–1602. 11. Taal BG, Hoefnagel CA, Valdes Olmos RA, Boot H, Beijnen JH. Palliative effect of metaiodobenzylguani- dine in metastatic carcinoid tumors. J Clin Oncol 1996; 14:1829–1838. 12. 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. 13. McDonald ML, Nagorney DM, Connolly HM, Nishimura RA, Schaff HV. Carcinoid heart disease and carcinoid syndrome: successful surgical treatment. Ann Thorac Surg 1999; 67:537–539.

ADDRESS: Emil Hayek, MD, Akron General Medical Center, 400 Wabash Avenue, Akron, OH 44307; e-mail hayeke@adel- phia.net.

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