Type III Apo E2/2 Dysbetalipoproteinemia Presenting with Rectal Hemorrhaging from Ischemic Colitis

A 64-year-old woman was hospitalized with abdominal pain and gastrointestinal (GI) hemorrhaging. She was severely anemic with marked elevation of both cholesterol and triglycerides. The patient was transfused. Colonoscopy revealed severe right-sided ischemic colitis. A two-dimensional (2-D) echocardiogram was normal and telemetry showed no arrhythmia. An aortogram did not show the cause of interruption of mesenteric blood flow to the colon, although irregularity and 50% stenosis of the abdominal aorta was noted. The colon did not infarct and she survived without requiring surgical resection.

Fasting lipids were normal prior to menopause. She developed hypothyroidism and cholesterol rose to 517 and triglycerides rose to 403. Her endocrinologist prescribed replacement Synthroid, Questran 4 gms and niacin 1500 mg. Within the next 10 years, she developed peripheral vascular disease (PVD), 50% stenosis of the abdominal aorta and life-threatening ischemic colitis.

The clinical presentation suggests Type III Dyspbetalipoprotinemia as expressed in patients with the Apo E 2//2 genotype, which in her case resulted in spontaneous recurring cholesterol emboli from aortic plaque to the colon. This lipid disorder is highly atherogenic, involves defective apolipoprotein E (apo E) rather than apolipoprotein B (apo B) and its receptor abnormalities, with fascinating paradoxes¹ and intriguing effects that go far beyond lipoprotein metabolism such as Alzheimer’s disease, HIV and Hepatitis C virus (HCV).²

Hypercholesterolemia is listed as a risk factor for ischemic colitis. Clinically, in a patient with hypercholesterolemia and ischemic colitis, one would expect blockage of mesenteric flow by plaque or emboli. However, if an aortogram were to be performed, flow in the mesenteric vessels will most often appear normal. Unexpectedly, massive caking of atherosclerotic plaque of the aorta may be seen. Although ischemic colitis in hypercholesterolemic and nonhypercholesterolemic individuals is thought to be caused primarily by low-flow states – as during dialysis or hypotensive shock^3,4 – emboli from aortic plaque have been found in submucosal arterioles of the stomach and colon in resected specimens and at autopsy. The arterioles are usually too deep to be seen on superficial biopsies and too small to be seen on angiography.⁵ GI complaints are usually vague and endoscopy may not recognize embolic ischemic gastric ulcers or gastric livido reticularis. A colonoscopy may misdiagnose ischemic changes as chronic ulcerative colitis. Only about 10% are recognized premortem.⁶

Severely elevated lipid values and responses to metabolic changes with diet in a recently menopausal woman with a frighteningly rapid atherogenic hyperlipoproteinemia (HLP) having elevated HDL cholesterol (HDL-C) with markedly elevated very-low-density lipoprotein cholesterol (VLDL-C) but normal glucose suggest Type III dysbetalipoprotinemia. Findings of xanthoma stratium palmare (XSP) which appear as orange creases of the palms of the hands and electrophoretic broad bands occur in less than 20% of cases. Isoelectric Focusing done at Rockefeller Research Institute confirmed the diagnosis of Phenotype E 2/2 Type III Beta Dyslipoproteinemia. Genotyping also is now available.⁸

The patient was treated with estrogen, thyroid, vitamin B12, folic acid, dietary modifications and fibrates, with evidence of plaque regression on subsequent aortograms.⁹ Currently, estrogen therapy would be considered controversial.^12,13,14

The most common cause of Type III HLP is fully expressed in only 1 in 50 of the 1% of carriers of Genotype E 2/2. The problems do not reside in abnormalities in apo B or its liver uptake receptors, but rather that the highest-affinity receptors are normal in number and function but cannot recognize lipoproteins that express the E 2/2 allele. These include both the meal-derived chylomicron and hepatic-secreted VLDL remnants. They are removed by other less efficient cellular receptors and fasting lipids may appear normal for decades. Hyperlipidemia is expressed only if new metabolic changes or mutations overwhelm the compensatory modalities when superimposed on the underlying defective E 2/2 genotype. Declining estrogen levels after menopause (increased synthesis, decreased receptors), hypothyroidism (decreased receptors), obesity and insulin resistance (increased synthesis) enhance apo E influence on synthesis, impairment of lipolysis and clearance.^3,8

In these patient cholesterol accumulates in the increasingly vast numbers of lingering and trapped metabolically deranged VLDL. Prolonged exposure to impaired lipolysis of abundant triglyceride drive downsizing and exchange for cholesterol to ever smaller and denser remnant particles with the cholesterol content shifting from 20 to 60% and approaching the size of large buoyant LDL. However, although similar in size, there are physical and functional changes that take place.¹⁰ The increased concentration of such particles may cause a gradient-driven diffusion of these particles into the sub-endothelial space, which in turn leads to increased atherosclerosis. Apo E, has multiple forms and functions. Three isoforms are seen on isoelectricfocusing lipoprotein electrophoresis. E3 is the most common form and considered the most normal in structure and function. E4 and E2 have opposing actions when secreted locally in the brain, in the liver, in plasma on lipoprotein metabolism.

The Apo E4/E4 genotype is associated with a 14-fold increase in risk for Alzheimer’s disease and other neurodegenerative diseases. Small amounts are secreted locally in brain tissue but become fragmented and leak into the cytosol, interfering with mitochondria and neuronal repair. In the liver, E4 promotes progression of HIV and HCV. The effect of E4 on lipoprotein metabolism is one of only minor lipid variations. Remarkably, in the laboratory, minor changes convert E4 to the normally structured and functioning E3 genotype.²

As opposed to E4, the E2 secreted in brain tissue delays Alzheimer’s disease by up to 30 years.¹¹ Other effects on the brain are not benign. E2 promotes generalized atherosclerosis, including vascular dementia via abnormal lipoprotein metabolism and atherogenic HLP. In the liver, E2 interferes with the lipid envelope of HCV and HIV, preventing their replication.² Over time, the patient became lax, fired her cook, began eating out at restaurants very frequently, resumed drinking two glasses of wine a day and gained 40 pounds. Niacin and then statins were prescribed, but her PVD progressed. At age 77, she required a left circumflex stent and, at age 92, replacement of a xanthomatous – not calcific – aortic valve. She did not develop either atherovascular dementia or Alzheimer’s Disease.

Disclosure statement: Dr. DuShey has no disclosures to report.