The plot thickens

Aortic stenosis is intriguing in light of the patient’s painless melena and hematochezia. Heyde syndrome is a phenomenon in which high shear stress causes a reduction in the size of von Willebrand factor predisposing to bleeding from submucosal angiodysplasia. However, Heyde syndrome has been reported to occur in the setting of severe or critical aortic stenosis and is unlikely to be the cause here. The patient needs to be examined with both upper and lower endoscopy to rule out gastrointestinal (GI) malignancy, gastric and esophageal varices, and painless peptic ulcers. High right ventricular systolic blood pressures along with echodense material in the inferior vena cava and right atrium suggest the possibility of malignancy with vascular invasion. Tricuspid regurgitation is consistent with high right-sided pressures. As left ventricular ejection fraction is reduced, some of the high right-sided pressures could also be attributable to left heart failure. CT findings of rectal wall thickening and perirectal lymph nodes could be attributable to cancer with locally metastatic disease. Blood loss caused by this cancer would explain the severe anemia on admission as well as the low ferritin level and the iron deficiency anemia. In this 70-year-old man who has not had routine health care maintenance, the leading diagnosis is colorectal cancer. However, the markedly elevated globulin gap and elevated INR strongly suggest another process (eg, multiple myeloma, other paraproteinemia) is also present.

INR remained elevated (1.5) despite vitamin K supplementation. Peripheral blood smear showed hypochromic and normocytic RBCs with moderate rouleaux formation (Figure 1). Intravenous pantoprazole and octreotide were started. Upper and lower endoscopy revealed multiple esophageal erosions and both a polypoid mass and an ulcer within the rectum with evidence of prior bleeding. The mass was resected and the ulcer biopsied.

On hospital  day 3, the patient was transfused another unit of packed RBCs. Hemoglobin level increased from 7.4 g/dL to 8.2 g/dL, but he began to complain of headache, blurred vision, and worsened chest pain. He did not have weakness, numbness, diplopia, dysphagia, or dysarthria. External examination and extraocular movements of both eyes were normal. Visual acuity was 20/25 bilaterally. Funduscopic examination revealed mild dilation of retinal veins and retinal hemorrhages (Figure 2).

Rouleaux formation occurs as excess cathodal proteins, such as immunoglobulins or fibrinogen, adhere to RBCs and cause the cells to stack together in long chains. Classically this is associated with multiple myeloma, but can occur with Waldenström’s macroglobulinemia and other cancers or infections. It can also occur as an artifact in smear preparation but the large globulin gap in this patient supports pathologic rouleaux formation.

Venous retinopathy with hemorrhages may occur with occlusion of the arterial supply (eg, as with carotid artery obstruction) but also with hyperviscosity syndrome (HVS). Vascular disturbances throughout the body play a major role in HVS, but these changes are most easily visualized in the retina. It is interesting that the patient’s headache and blurred vision began after he received additional blood transfusions. Spuriously low hemoglobin and hematocrit levels may stem from increased plasma volume from high immunoglobulin M (IgM) concentrations in Waldenström macroglobulinemia; thus, RBC transfusions can exacerbate symptoms by elevating total RBC mass. Normocytic, normochromic anemia is characteristic of both multiple myeloma and Waldenström’s macroglobulinemia. That the patient’s chest pain recurred coincidentally with blurred vision and headache suggests the likely cause is cardiac ischemia from hyperviscosity. The serum viscosity level should be checked, and, if it is elevated, urgent serum plasmapheresis should be considered. Determining the source of excess globulin production and treating the underlying disease are crucial at this juncture.

In the general population, rectal adenocarcinoma is the most common cause of a rectal mass. In this patient, presence of a paraproteinemia may point to a different diagnosis. Extramedullary colorectal plasmacytoma can occur in the rectum but is exceedingly rare. Waldenström’s macroglobulinemia, a subtype of lymphoplasmacytic lymphoma, can be associated with a rectal lymphoma. At this point, it is not possible to confidently predict the etiology of the mass.

He was started on cyclophosphamide, bortezomib and dexamethasone for IgG κ myeloma with improvement in his headache, blurred vision, chest pain, and plasma viscosity (4 to 1.8). His hemoglobin remained stable at 10 g/dL. Neoadjuvant Capecitabine and radiation therapy were initiated for his rectal cancer.

Multiple myeloma is characterized by monoclonal proliferation of plasma cells, elevated circulating monoclonal immunoglobulin, and end-organ damage.¹ It accounts for approximately 0.8% of all new cancer diagnoses; average age at onset is 70 years. The patient described here had an unusual presentation, with GI bleeding and progression to HVS, and known risk factors for multiple myeloma (male sex, low socioeconomic status, welding career).^2,3

An early clue in the diagnosis was the patient’s large gamma gap and concurrent anemia. Gamma gap, calculated by subtracting serum albumin from serum total protein, is so named because it often reflects an elevated gamma globulin concentration. However, it actually reflects all nonalbumin serum protein. A gamma gap larger than 3.1 g/dL is an independent risk factor for death⁴ and may be associated with infection, autoimmunity, and malignancy. Although there are no screening guidelines for multiple myeloma, 73% of cases are brought to attention by anemia discovered on routine laboratory investigation.⁵ This patient’s lack of prior medical care likely contributed to his atypical presentation. Screening colonoscopy, recommended at age 50, might have identified his rectal cancer at an earlier stage.

The patient’s anemia was likely secondary to GI hemorrhage and bone marrow suppression. His hematochezia might have been partly related to the pathophysiologic interaction of paraproteins with platelets, coagulation factors, and blood vessels.⁶ Amyloidosis of the GI tract is seen in 8% of AL amyloidosis⁷ and most frequently manifests as gastrointestinal bleeding, which is thought to be due to ischemia, vascular friability, or mucosal lesions. It less commonly presents as malabsorption or dysmotility.⁸ Although gastrointestinal amyloid is not typically associated with radiologic abnormalities, occasionally it may cause luminal wall thickening, adenopathy, and inflammatory stranding.⁹ The gold standard for diagnosis is tissue biopsy. However, presence of amyloidosis does not change the overall treatment strategy for multiple myeloma.

An interesting feature of this case is the development of HVS, which typically manifests with mucosal bleeding, blurred vision, and headache.¹⁰ HVS can be diagnosed on retinal examination with findings of venous tortuosity, dilatation, and intraretinal hemorrhage, as occurred in this case,¹¹ and is confirmed with serum viscosity measurement. The first evidence of HVS in this case might have been the spontaneous echo contrast, or “smoke,” detected on echocardiogram. Spontaneous echo contrast represents increased RBC aggregation, from interaction of RBCs and plasma proteins, at low shear rates,¹² and is associated with conditions that result in left atrial stasis, such as atrial arrhythmias and mitral stenosis. This patient did not have valvular pathology or arrhythmia, and thus the “smoke” likely reflected HVS.

Of the paraproteinemias, Waldenström’s macroglobulinemia is most often associated with HVS, likely because of the pentameric structure of IgM¹³ and the consequential large size that predisposes to vascular occlusion. Whereas HVS can occur with IgM levels as low as 3 g/dL, it typically does not occur with IgG concentrations under 15 g/dL. This patient presented with an IgG level of 8 g/dL and developed HVS symptoms only after multiple packed RBC transfusions. Elevated IgG level likely made him susceptible to HVS, which ultimately was precipitated by blood transfusion. Therefore, this patient’s initial chest pain most likely was caused by demand cardiac ischemia secondary to anemia, whereas his subsequent, posttransfusion chest pain likely resulted from hyperviscosity angina. Hyperviscosity angina—cardiac ischemia resulting from poor coronary perfusion caused by hyperviscous blood—has been described in polycythemia and connective tissue disorders.^14,15 To our knowledge, however, hyperviscosity angina has not been reported in patients with multiple myeloma. Treatment of hyperviscosity with end-organ damage typically consists of plasmapheresis, but this patient was started on urgent chemotherapy, and his symptoms improved. Untreated HVS can lead to end-organ ischemia and death.

This patient had a multitude of seemingly disparate symptoms and abnormalities that ultimately were united in a diagnosis of IgG κ multiple myeloma. Subsequently diagnosed rectal adenocarcinoma may have led to ongoing blood loss, which worsened the anemia, but had no evident relation to the primary diagnosis of multiple myeloma. This case exemplifies the fact that HVS is a rare but important iatrogenic complication of multiple myeloma treated with blood transfusion. As this patient’s hospital course progressed, the plot, and his blood, thickened.