Clinical Summary
This is the case of a 43 year old Hispanic woman with more than a 20 years history of diabetes mellitus, hypertension, congestive heart failure, and gastritis associated with Helicobacter pylori infection. She developed nephropathy, neuropathy and retinopathy secondary to her diabetes, and was legally blind and wheelchair bound. She was brought to the hospital after 24 hours of localized colic-type epigastric pain, nausea and vomiting of “coffeeground” material. Her medications before admission included NPH insulin, furosemide and atenolol.
This is the case of a 43 year old Hispanic woman with more than a 20 years history of diabetes mellitus, hypertension, congestive heart failure, and gastritis associated with Helicobacter pylori infection. She developed nephropathy, neuropathy and retinopathy secondary to her diabetes, and was legally blind and wheelchair bound. She was brought to the hospital after 24 hours of localized colic-type epigastric pain, nausea and vomiting of “coffeeground” material. Her medications before admission included NPH insulin, furosemide and atenolol.
Significant findings on her physical exam were: Vital signs BP 168/94, HR 86, RR 12, T 37°C. Heart: normal S1S2 and an S3 with no murmurs. Clear lungs. Abdomen: bowel sounds present; distended and soft with mild tenderness, no guarding and no rebound. Positive stool test for blood. Extremities: bilateral pretibial edema, left foot with healing ulcer on plantar surface, and the right first toe tip had evidence of dry gangrene. Neurologic: blind; decreased sensation on both lower extremities knee to footdistribution (stocking).
Laboratory data and other tests
Laboratory: WBC 19 (S 90%, L 5%), Hct 37, Plt 270; PT/PTT 10/29; amylase 6.1; glucose 320; BUN/creat 37/1.3; UA pH 7, protein 300, glucose 1000, WBC/RBC 3/heavy, bacteria 5-10 and epithelial cells 10-20/HPF.
Laboratory: WBC 19 (S 90%, L 5%), Hct 37, Plt 270; PT/PTT 10/29; amylase 6.1; glucose 320; BUN/creat 37/1.3; UA pH 7, protein 300, glucose 1000, WBC/RBC 3/heavy, bacteria 5-10 and epithelial cells 10-20/HPF.
The patient continued to vomit, the bloody diarrhea persisted and the bowel sounds diminished. Infection or ischemic bowel disease were the clinical diagnoses considered. An abdominal CT-scan showed occlusion consistent with thrombus in the superior mesenteric artery (SMA), which was confirmed by angiography. Thrombectomy of the SMA and Goretex patch angioplasty were performed. In addition, the patient was transfused. Soon after surgery, acute renal failure developed. Hemodialysis and anticoagulation therapy were started. However, 10 days later she had an episode of gastrointestinal bleeding and the heparin was discontinued. The following day the blood pressure suddenly dropped and the patient expired.
Gross Description
The heart weighed 500 g and showed dilatation of the right and left atria, and hypertrophy of the left ventricle (1.6 cm in thickness). The tricuspid valve measured 12.6 cm in length. The coronary arteries were partially occluded (60–90%) by atherosclerosis with calcification. The aorta had moderate atherosclerosis. The lungs were congested (850 g combined). Two ulcers were noted in the body of the stomach, each measuring 1 cm in iameter. The distal portion of the jejunum and the proximal portion of the ileum had serosal purple discoloration consistent with ischemic bowel disease. The luminal content was bloody. The vascular graft of the superior mesenteric artery was partially occluded by a thromboembolus. The kidneys weighed 450 g combined and had a finely granular surface. The cut surface was unremarkable.
The heart weighed 500 g and showed dilatation of the right and left atria, and hypertrophy of the left ventricle (1.6 cm in thickness). The tricuspid valve measured 12.6 cm in length. The coronary arteries were partially occluded (60–90%) by atherosclerosis with calcification. The aorta had moderate atherosclerosis. The lungs were congested (850 g combined). Two ulcers were noted in the body of the stomach, each measuring 1 cm in iameter. The distal portion of the jejunum and the proximal portion of the ileum had serosal purple discoloration consistent with ischemic bowel disease. The luminal content was bloody. The vascular graft of the superior mesenteric artery was partially occluded by a thromboembolus. The kidneys weighed 450 g combined and had a finely granular surface. The cut surface was unremarkable.
Microscopic Description
The cardiovascular examination confirmed right and left ventricular hypertrophy with mild perivascular fibrosis and multifocal interstitial and replacement fibrosis. Sections from the superior mesenteric artery and its branches revealed medial calcific sclerosis (Monckeberg’s) with recent hemorrhage in the portion where fragments of synthetic graft were identified. The lumen was 60% occluded by a hyaline plaque showing signs of remote and recent hemorrhage.
The cardiovascular examination confirmed right and left ventricular hypertrophy with mild perivascular fibrosis and multifocal interstitial and replacement fibrosis. Sections from the superior mesenteric artery and its branches revealed medial calcific sclerosis (Monckeberg’s) with recent hemorrhage in the portion where fragments of synthetic graft were identified. The lumen was 60% occluded by a hyaline plaque showing signs of remote and recent hemorrhage.
Sections from the lung revealed congestion as well as numerous hemosiderin-laden macrophages, the so called ‘heart failure cells’, and signs of mild pulmonary hypertension. The small bowel had segments of transmural ischemic and hemorrhagic infarction with focal areas of mucosal regeneration. The kidneys exhibited areas of nodular and diffuse glomerulosclerosis (Kimmelstiel-Wilson). The central nervous system revealed acute hippocampal hypoxic and degenerative changes. The remaining organs were unremarkable; except for the liver which showed mild steatosis and centrilobular congestion.
Case Analysis
This case classically depicts a number of features of diabetic cardiovascular disease. The patient had Type I, insulin-dependent diabetes mellitus (IDDM, juvenile onset) for more than 20 years, with hypertension, and complications affecting multiple organ systems. Primarily, she had diffuse vascular disease affecting a wide range of different caliber blood vessels, from the smallest to the largest. This is a crucial feature of longstanding diabetes for 10 or more years, whether it is insulin dependent or not (types I and II, respectively), and particularly when it is associated with systemic hypertension. Even the autonomic and peripheral diabetic neuropathy, which has been associated with metabolic derangements that affect neural transmission, may have an ischemic component mediated by microvascular damage to nerve fibers.
This case classically depicts a number of features of diabetic cardiovascular disease. The patient had Type I, insulin-dependent diabetes mellitus (IDDM, juvenile onset) for more than 20 years, with hypertension, and complications affecting multiple organ systems. Primarily, she had diffuse vascular disease affecting a wide range of different caliber blood vessels, from the smallest to the largest. This is a crucial feature of longstanding diabetes for 10 or more years, whether it is insulin dependent or not (types I and II, respectively), and particularly when it is associated with systemic hypertension. Even the autonomic and peripheral diabetic neuropathy, which has been associated with metabolic derangements that affect neural transmission, may have an ischemic component mediated by microvascular damage to nerve fibers.
The classification of blood vessel calibers by size as macrovascular, small, and microvascular is an arbitrary one, and varies between investigators. Nevertheless, it is useful because pathological injury is generally limited to one class of vessel (e.g. atherosclerosis affects the macrovasculature), and tissue damage may depend on the size of the vessel affected in the process. In general, macrovascular blood vessels are the major elastic capacitance vessels including the aorta and the iliac arteries (these have a media composed of multiple lamellae or layers of elastic tissue and smooth muscle cells), and the muscular arteries including the aortic branch vessels (e.g. coronary, carotid, femoral, popliteal, renal, celiac, superior mesenteric, etc.). The muscular arteries have an intima separated from the media by an internal elastic lamella, and the media is composed of smooth muscle tissue. The macrovasculature is primarily affected by atherosclerosis. Microvascular vessels are the small arteries below 100-200 µm (micrometers or microns), although some investigators would consider vessels beginning at 50-100 µm and smaller. The microvasculature includes vessels identified as arterioles, capillaries, and venules. These vessels are affected by smooth muscle hypertrophy, and increased connective tissue deposition (fibrillar and nonfibrillar collagen).
In diabetes mellitus, it is common to find increased basement membrane material surrounding capillaries, and intercalated around smooth muscle cells in the media of small vessels. In addition, the microvasculature may have endothelial cell dysfunction, and hyper-reactivity (e.g. spasm) of the endothelial and smooth muscle cells, which may lead to tissue damage. The small vessels are arteries with calibers ranging between 50-100 µm and 1000 µ. These are muscular vessels, easily identified by microscopic tissue examination, that are generally affected by “sclerosis” not atherosclerosis. This means that they are ‘stiffer’ or hardened (literal definition of sclerosis) due to the deposition of connective tissue and smooth muscle hyperplasia. The end-result is an increase in resistance to blood flow, and with severe proliferative changes, there is decreased luminal caliber, thereby causing chronic obstruction and tissue ischemia. Essentially, diabetic vascular injury is ubiquitous and diffuse, eventually affecting all blood vessels, leading to extensive tissue and multiorgan damage.
The patient in this case had macrovascular disease with significant atherosclerosis of coronary arteries, the aorta and its branches. It was the disease of the superior mesenteric artery that precipitated the ischemic bowel disease, requiring surgical intervention. Histologically, there was an atherosclerotic plaque with remote and recent hemorrhage, which can trigger vascular instability or dynamic changes in the vessel, leading to acute luminal occlusion (thrombosis) and subsequent ischemia. There were also changes of sclerosis, with features of Monckeberg’s medial sclerosis and calcification. This is a degenerative change that involves the internal elastic lamella with spread of calcium and scar tissue into the media. Monckeberg’s medial sclerosis is a common finding in diabetic patients, particularly in the lower extremities where it may lead to vascular insufficiency and gangrene.
She had evidence of small vessel disease, with thickened small arteries in the heart, and in the kidneys. The latter are associated with arterionephrosclerosis secondary to hypertension, which leads to chronic cortical ischemia, scarring, and renal dysfunction. Although her renal dysfunction was also related to microvascular disease, it is not uncommon in diabetic patients to develop ischemia due to vascular pathology affecting all sizes of vessels (e.g. renal artery, small arteries, arterioles, and capillaries). In the heart, small artery disease may lead to focal areas of ischemia with subsequent scarring, which may contribute to the hypertensive and diabetic cardiomyopathy (see below). The ulceration and dry gangrene on her extremities may also have been secondary to disease of small arteries in the muscle and skin.
There was also evidence of microvascular disease in different organs. She had retinopathy leading to blindness. This is often secondary to rupture of capillary microaneurysms with retinal and vitreous hemorrhage and proliferation of new vessels and scar tissue obliterating the retina (e.g. proliferative retinopathy). Ischemic damage may also result from hypertensive sclerosis and narrowing of arterioles. In the kidney, in addition to hypertensive arterionephrosclerosis, she had nodular diabetic glomerulosclerosis or Kimmelstiel-Wilson disease. The latter causes marked nodular thickening and ultimate obliteration of glomerular capillary loops. Only recently has it been shown to be secondary to damage to the glomerular capillaries leading to microaneurysms with ultimate thrombosis and reorganization. These microaneurysms, which occur due to localized injury to the capillary endothelial cells with outpouching of the lumen, are similar to those found in the eye and in the heart.
The patient had a clinical history of congestive heart failure, and her heart was hypertrophied (500 g, normal up to 350 g), with microscopic changes of interstitial and replacement fibrosis. The left and right ventricles were hypertrophied. These findings were characteristic of hypertensive and diabetic cardiomyopathy, with thick-walled chambers and microscopic scarring. Pathophysiologically, the chamber dimensions are small (e.g. decreased end-diastolic volume), and generally the contractility of the ventricle is normal or super-normal. The congestive heart failure symptoms result from diastolic dysfunction. The ventricles are stiff with poor compliance; they pump adequately but fill poorly. As seen in the present case, the description of the ventricular chamber sizes, and the dilation of both atria are typical of a heart with diastolic dysfunction (the atria dilate because of the poor compliance of the ventricles).
The pathogenesis of hypertensive and diabetic cardiomyopathy is complex and multiple factors contribute to its development. Though the diabetic heart is often affected by significant coronary artery atherosclerosis, large vessel ischemia may not be sufficient to account for the disease. In this patient, there was no evidence of large areas of scarring secondary to coronary artery disease. However, small vessel sclerosis certainly contributes to microscopic areas of scarring. These hearts have significant microvascular disease, with microaneurysms present in arterioles and capillaries (Figure 1). In addition, the microvasculature is hyper-reactive (e.g. spasm) and leads to multiple areas of reperfusion damage in the myocardium, with eventual replacement by scar tissue (Figures 2 and 3). Finally, the effects of hypertension also lead to hypertrophy of myocardial cells. The combination of scar tissue and hypertrophy contributes the major component of the diastolic dysfunction, although metabolic cellular considerations (e.g. poor relaxation of cells due to abnormal calcium flux) also play a role.
Figure 1 Silicone rubber (Microfil) perfused diabetic heart after "clearing" the tissue so that it is semi-translucent. The microcirculation vessels are examined with epi-illumination, thereby providing a 3-dimensional appearance. There are several fusiform microaneurysms (arrows) in arterioles and capillaries characteristic of diabetic human hearts, and similar to microaneurysms in the diabetic retina and renal glomerulus (30x).
Figure 2 Silicone rubber (Microfil) perfused diabetic heart photographed with trans-illumination. This field shows aneurysmically dilated capillaries with focal narrowing (arrow) consistent with microvascular spasm that persisted after death (30x).
Figure 3 Left ventricular cross section demonstrating typical features of hypertensive and diabetic cardiomyopathy. There is left ventricular hypertrophy, extensive multifocal myocytolytic necrosis (the darker areas in the subendocardium and mid-wall), and multifocal fibrosis (the paller areas involving the papillary muscle, trabeculae, and ventricular wall). The recent and organizing necrosis, together with remote scarring, leads to replacement of large areas of functional myocardium, equivalent to myocardial infarction.
Despite the fact that the immediate cause of death in this patient could be directly attributed to the mesenteric artery thrombosis, and bowel ischemia, there was significant evidence for systemic disease affecting multiple organs. This is a very typical scenario in diabetic patients, because the disease affects vessels of all calibers, leading to tissue damage throughout the body.
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