Hyperlipidemia Case Study

CLINICAL DIABETES
VOL. 17 NO. 4 1999


CASE STUDIES


Case Study: A 55-Year-Old Man With Obesity, Hypertriglyceridemia, and Newly Diagnosed Type 2 Diabetes Who Collapsed and Died

Deborah Thomas-Dobersen, RD, MS, CDE, and Michael J. Dobersen, MD, PhD


Presentation
A 55-year-old Caucasian man presented with polyuria, polydipsia, and "feeling dry" during the past 2 months. His medical history was remarkable for a 3-year history of poorly controlled hypertriglyceridemia. His initial fasting serum cholesterol was 299 mg/dl, triglycerides were 928 mg/dl, and high-density lipoprotein (HDL) cholesterol was 30 mg/dl before treatment.

He was treated with gemfibrozil (Lopid) 600 mg twice daily and told to watch his diet and exercise. No referral was made to a registered dietitian.

Two years later, a fasting triglyceride level of 570 mg/dl prompted further increase of gemfibrozil to 600 mg three times daily (this exceeds usual recommended dosing). The patient took no other medications and denied drinking alcohol and smoking.

Physical examination revealed a height of 5'11", weight of 240 lb (body mass index [BMI] of 34.4 kg/m2), blood pressure of 150/88 mm Hg, and pulse of 80/min. There was no abdominal tenderness or organomegally. Laboratory evaluation showed a serum glucose of 397 mg/dl. Urinalysis revealed 3+ glucose and negative ketones.

The patient was started on 5 mg glyburide [Micronase] daily. He was also given a referral to a dietitian. That evening, the patient complained of abdominal pain, nausea, vomiting and flu-like symptoms. He collapsed at home and died a short time later. At autopsy, it was found that he died of acute hemorrhagic pancreatitis. The patient was also found to have severe arteriosclerotic cardiovascular disease with severe two-vessel coronary artery atherosclerosis.

Questions
1. What is a normal level of serum triglyerides?
2. What is the medical nutrition therapy for hypertriglyeridemia?
3. What are current recommendations for screening for diabetes?
4. What effect did the onset of diabetes have on this patient's hypertriglyc- eridemia?

Commentary
The National Cholesterol Education Program (NCEP) Adult Treatment Panel II1 gives the following classification for triglyerides:

normal                         200 mg/dl
borderline high             200–400 mg/dl
high                             400–1,000 mg/dl
very high                      >1,000 mg/dl

Hypertriglyceridemia can be primary (associated with familial hypertriglyceridemia) or secondary (due to diabetes mellitus, hypothyroidism, kidney disease, or medication). Important exacerbating factors are obesity and excess alcohol intake.

Hypertriglyceridemia and low HDL cholesterol (<35 mg/dl) are commonly seen in the insulin resistance syndrome, or Syndrome X. In fact, an increase in plasma triglyceride is the most common metabolic characteristic of Syndrome X. Although all insulin-resistant patients do not develop type 2 diabetes, many do. Insulin resistance is involved in the pathogenesis and clinical course of type 2 diabetes as well as hypertension and coronary heart disease.2

In type 2 diabetes, a common abnormal lipid pattern is an elevation of very-low-density lipoprotein (VLDL) cholesterol, a reduction in HDL, and a low-density lipoprotein (LDL) cholesterol that contains a greater proportion of small, dense atherogenic LDL particles.3 Diabetes, as a possible cause of the hypertriglyceridemia, should be evaluated and treated if found, as several studies have shown that this pattern of dyslipidemia precedes the onset of type 2 diabetes mellitus.4

The goals for medical nutrition therapy, the first line of treatment1 for borderline to high triglyceride values, are:

1. weight loss if indicated
2. restriction of alcohol intake
3. increased physical activity
4. the American Heart Association (AHA) Step 1 progressing to Step 2 diets, individualized for the patient

A weight loss of only 5% of total body weight effectively lowers triglycerides. Exercise can lower triglycerides by approximately 10%. If triglycerides increase on the AHA Step 2 meal plan, the amount of carbohydrate should be decreased and the amount of mono-unsaturated fats increased. At present, it is still controversial whether this has a long-term or a short-term benefit.

The NCEP Adult Treatment Panel noted that the expertise of a registered dietitian is very helpful in achieving adherence with these protocols.1 When referring a patient to a dietitian, include laboratory data on hyperlipidemia.

People with triglycerides >500 mg/dl are at risk of pancreatitis. This risk increases as triglycerides increase, becoming very high when serum triglycerides approach 2,000 mg/dl.5 Special immediate attention to lower triglycerides to <400 mg/dl is recommended. Severe dietary fat restriction (<10% of calories) in addition to pharmacological therapy is needed to reduce the risk of pancreatitis,3 as gemfibrozil will not be able to decrease serum triglycerides when they are extremely high (>1,500 mg/dl). This severe diet can decrease serum triglycerides by 20–25%. Further reduction to Adult Treatment Panel II goals of <200 mg/dl may be beneficial.

This patient's triglyceride level was inadequately treated. The patient did not make some follow-up appointments, and the dyslipidemia may have been refractory to treatment.

The onset of type 2 diabetes in this patient may have deleteriously raised the serum triglyceride levels in two ways: by directly increasing VLDL production and by decreasing catabolism due to decreased lipoprotein lipase activity. Several assumptions must be made at this point to understand the onset of acute hemorrhagic pancreatitis. It is reasonable to assume that the triglyceride level soared to >1,000 mg/dl sometime during the onset of the type 2 diabetes. It is also reasonable to assume that the actual onset of diabetes predated the onset of symptoms by several months, possibly a year. If diabetes had been detected, improved glycemic control would have been very effective in reducing serum triglycerides.

The exact mechanism whereby hypertriglyceridemia causes pancreatitis is unknown. Presumably, the extremely high level of serum triglycerides causes "sludging" in the pancreatic vasculature, resulting in ischemia and necrosis. Alternatively, pancreatic lipase breaks down triglycerides to free fatty acids, which at high levels can also cause pancreatitis by direct toxicity (personal communication, Robert H. Eckel, MD, Lipid Research Clinic, University of Colorado Health Sciences Center, Denver, Colo.).

Diabetes occurs more frequently in individuals with hypertriglyceridemia (>250 mg/dl) and/or an HDL level of <35 mg/dl, in patients who are obese (BMI >27 kg/m), and in people over the age of 45.6 The American Diabetes Association has recommended that screening for diabetes may be appropriate for individuals with one or more risk factors.6 This patient had three risk factors. The recommended screening interval is 3 years.

More aggressive treatment of hypertriglyceridemia and earlier detection of diabetes may have lessened the impact of the onset of diabetes on triglyceridemia, thereby preventing the premature death of this patient. A referral to a lipid specialist may have helped in treating this severe, complex, or refractory disorder. An inadequate understanding of the importance of weight loss, exercise, and diet changes may have prevented a satisfactory lowering of serum triglycerides.

Clinical Pearls
1.  Hypertriglyceridemia should be carefully monitored and aggressively treated by weight loss, diet, exercise, alcohol restriction, and pharmacological means to keep serum levels <400 mg/dl to prevent possible pancreatitis and <200 mg/dl to prevent coronary heart disease.

2.  Patients presenting with lipid patterns similar to those found in type 2 diabetes (high triglycerides and low HDL) should be screened for diabetes.

3.  Medical nutrition therapy is the cornerstone of treatment for hyperlipidemia. Referral to a registered dietitian and a lipid specialist is recommended to help with such severe dyslipidemia.


REFERENCES

1National Cholesterol Education Program (NCEP) Expert Panel: Summary of the second report of the NCEP expert panel on detection, evaluation, and treatment of high blood cholesterol (Adult Treatment Panel II). JAMA 269:3015-23, 1993.

2Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988.

3American Diabetes Association: Position statement: Management of dyslipidemia in adults with diabetes. Diabetes Care 22:S56-59, 1999.

4Haffner SM: Management of dyslipidemia in adults with diabetes: Technical review. Diabetes Care 22:160-78, 1998.

5Grundy SM, Vega GL: Two different views of the relationship of hypertriglyeridemia to coronary heart disease. Arch Intern Med 152:28-34, 1992.

6American Diabetes Association: Position statement: Screening for type 2 diabetes. Diabetes Care 22:S20-23, 1999.


Deborah Thomas-Dobersen, RD, MS, CDE, is in private practice, and Michael J. Dobersen, MD, PhD, is a forensic pathologist at the Arapahoe County Coroner's Office, in Littleton, Colo.


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Case Details

A 45-year-old man presented to the emergency with chest pain. The chest pain lasted for approximately 15 minutes then subsided on its own. He also noticed that he was nauseated and was sweating during the pain episode. He had no medical problems and had not been to a physician for several years.

On examination, he was in no acute distress with normal vital signs. His lungs were clear to auscultation bilaterally, and his heart had a regular rate and rhythm with no murmurs. An electrocardiogram(ECG) revealed slight ischemic changes. The blood biochemistry revealed raised serum total cholesterol and LDL cholesterol levels.  He was placed on a low-fat diet and Lovastatin therapy.

He was without complaints and was feeling well on his subsequent follow-up visit. On repeat serum cholesterol screening, a decrease in the cholesterol level was noted.

What is the mechanism of action of this drug?

What are the potential side effects?

What are the alternative options to treat this patient?

Case discussion

The patients had an episode of IHD (Ischemic heart disease), and had hyperlipidemia.

Hyperlipidemia is one of the most treatable risk factors of coronary heart disease. Initially, when the fasting low-density lipoprotein (LDL) cholesterol is found elevated, life style modification is recommended such as dietary adjustments, exercise, and weight loss. If the LDL cholesterol level is again found above threshold, pharmacological therapy is initiated. Since the patient in the given case had a mild attack of IHD, hence without trial he had been put on low-fat diet and statins.

Basic concept

A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the remainder is provided by the average diet. The liver and intestine account for approximately 10% each of total synthesis in humans. Virtually all tissues containing nucleated cells are capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol. LDL-C is a transporter of cholesterol from liver to peripheral tissues, while HDL is a transporter of cholesterol from peripheral tissues to liver for degradation. Excess LDL is responsible for Atherosclerosis and is a risk factor for IHD ( Ischemic heart disease), that is why it is considered “Bad cholesterol”. HDL-C on the other day acts as a scavenger to lower serum cholesterol level, because of this, it is cardio protective and is considered ‘Good cholesterol”.

Biosynthesis of cholesterol

The biosynthesis of cholesterol may be divided into five steps: (1) Synthesis of Mevalonate from acetyl-CoA. (2) Formation of isoprenoid units from Mevalonate by loss of CO2. (3) Condensation of six isoprenoid units form squalene. (4) Cyclization of squalene gives rise to the parent steroid, lanosterol. (5)Formation of cholesterol from lanosterol.

Hypercholesterolemia and the consequences

Atherosclerosisis characterized by the deposition of cholesterol and cholesteryl ester fromthe plasma lipoproteins into the artery wall. Diseases in which prolonged elevated levels of VLDL, IDL, chylomicron remnants, or LDL occur in the blood (e.g.,diabetes mellitus, lipid nephrosis, hypothyroidism, and other conditions of hyperlipidemia) are often accompanied by premature or more severe atherosclerosis. There is also an inverse relationship between HDL (HDL2) concentrations and coronary heart disease, making the LDL: HDL cholesterol ratio a good predictive parameter. This is consistent with the function of HDL in reverse cholesterol transport.

Diet Can Play an Important Role in Reducing Serum Cholesterol

Hereditary factors play the greatest role in determining individual serum cholesterol concentrations; however, dietary and environmental factors also play a part,and the most beneficial of these is the substitution in the diet of polyunsaturatedand monounsaturated fatty acids for saturated fatty acids. Plant oils such as corn oil and sunflower seed oil contain a high proportion of polyunsaturated fatty acids, while olive oil contains a high concentration of monounsaturated fatty acids. On the other hand, butter fat, beef fat, and palm oil contain a high proportion of saturated fatty acids. Sucrose and fructose have a greater effect in raising blood lipids, particularly triacylglycerols, than do other carbohydrates.

The reason for the cholesterol-lowering effect of polyunsaturated fatty acids is still not fully understood. It is clear, however, that one of the mechanisms involved is the up-regulation of LDL receptors by poly- and monounsaturated ascompared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic.

Lifestyle and the Serum Cholesterol Level

Additional factors considered to play a part in coronary heart disease include high bloodpressure, smoking, male gender, obesity (particularly abdominal obesity), lack of exercise, and drinking soft as opposed to hard water. Premenopausal women appear to be protected against many of these deleterious factors, and this is thought to be related to the beneficial effects of estrogen. There is an association between moderate alcohol consumption and a lower incidence of coronary heart disease. This may be due to elevation of HDL concentrations resulting from increased synthesis of apo A-I. It has been claimed that redwine is particularly beneficial, perhaps because of its content of antioxidants.Regular exercise lowers plasma LDL but raises HDL.

Hypolipidemic Drugs

When diet changes fail, hypolipidemic drugs are prescribed to reduce Serum Cholesterol & Triacylglycerol levels. Few of the commonly used drugs to lower cholesterol level are as follows-

1) Statins (Lovastatin)

A family of drugs known as statins, have proved highly efficacious in lowering plasma cholesterol and preventing heart disease.

Mechanism of action of drug -Lovastatin is a member of a class of drugs (Atorvastatin, fluvastatin, pravastatin and Simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase.

These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins arebound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Effective treatment with Lovastatin, along with low fat diet, decreases levels of blood cholesterol. The lowering of cholesterol also lowers the amounts of the lipoproteins that transport cholesterol to peripheral tissues i.e. low density lipoproteins(LDL).

Side effects of therapy –The potential side effects include elevated liver function tests,increased muscle creatine phosphokinase (CPK) secondary to Myopathy and rarely rhabdomyolysis.

2) Alternative treatment options-Other agents that may be considered include bile acid sequestrants,Niacin, fibric acid, and fish oils.

a) Niacin is a vitamin that is used in high doses to treat hypercholesterolemia. Niacin acts to decrease VLDL and LDL plasma levels.Its mechanism of action is not clearly understood but probably involves inhibition of VLDL secretion, which in turn decreases the production of LDL. Niacin inhibits the release of free fatty acids from adipose tissue which leads to a decrease of free fatty acids entering the liver and decreased VLDL synthesis in the liver. This decreases the availability of VLDL for conversion to LDL (containing cholesterol esters). Niacin also increases high-densitylipoprotein (HDL) (the “good cholesterol”) by an unknown mechanism.

b) Fibrates such as Clofibrate and gemfibrozil act mainly to lower plasma triacylglycerols by decreasing the secretion of triacylglycerol and cholesterol-containing VLDL by the liver.

c) Ezetimibe– a new drug, Ezetimibe, which reduces blood cholesterol levels by inhibiting the absorption of cholesterol by the intestine, has recently been introduced. Ezetimibe belongs to the azetidinone class of cholesterol absorption inhibitors.

d) Bile Acid Sequestrants (Resins)-Bile acid sequestrants bind bile acids in the intestine and promote their excretion in the stool. To maintain the bile acid pool size, the liver diverts cholesterol to bile acid synthesis. The decreased hepatic intracellular cholesterol content results in up regulation of the LDL receptor and enhanced LDL clearance from the plasma. Bile acid sequestrants include Cholestyramine, colestipol, and colesevelam.

e) Omega 3 Fatty Acids (Fish Oils)-ω-3 polyunsaturated fatty acids (ω -3 PUFAs) are present in high concentration in fish and in flax seeds. The most widely used ω -3 PUFAs for the treatment of hyperlipidemia are the two active molecules in fish oil: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oils can result in an increase in plasma LDL-C levels in some patients. Fish oil supplements can be used in combination with Fibrates,niacin, or statins to treat hypertriglyceridemia. In general, fish oils are well tolerated and appear to be safe, at least at doses up to 3–4 g. A lower dose of omega 3 (about 1 g) has been associated with reduction in cardiovascular events in CHD (Chronic Heart Disease) patients and is used by some clinicians for this purpose.

Management of Low HDL-C

 Causes of low HDL levels

·        Severely reduced plasma levels of HDL-C(<20 mg/dL) accompanied by triglycerides <400 mg/dL usually indicate the presence of a genetic disorder, such as a mutation in apoA-I, LCAT(Lecithin Cholesterol Acyl Transferase) deficiency,or Tangier disease.

·        HDL-C levels <20 mg/dL are common in the setting of severe hypertriglyceridemia, in which case the primary focus should be on the management of the triglycerides.

·        HDL-C levels <20 mg/dL also occur in individuals using anabolic steroids.

·        Secondary causes of moderately low levels of plasma HDL (20–40 mg/dL) should be considered in conditions like smoking, Type 2 Diabetes mellitus, Gaucher’s disease and malnutrition.

Management

 1) Smoking should be discontinued.

2) Obese persons should be encouraged to lose weight, sedentary persons should be encouraged to exercise.

3) Diabetes should be optimally controlled. 

4) When possible,medications associated with reduced plasma levels of HDL-C should be discontinued. 

5)The presence of an isolated low plasma level of HDL-C in a patient with a borderline plasma level of LDL-C should prompt consideration of LDL lowering drug therapy in high-risk individuals. 

6) Statins increase plasma levels of HDL-C only modestly (~5–10%). 

7) Fibrates also have only a modest effect on plasma HDL-C levels (increasing levels ~5–15%), except in patients with coexisting hypertriglyceridemia, where they can be more effective. 

8) Niacin is the most effective available HDL-C–raising therapeutic agent and can be associated with increases in plasma HDL-C by up to ~30%, although some patients do not respond to niacin therapy.

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