Primary Hyperlipoproteinaemias (Types I, IV & V) in which Hypertriglyceridaemia Predominates

Severe hypertriglyceridaemia (types I and V)
For a review of severe hypertriglyceridaemia see references [Durrington, 1995a; Brunzell, 1995].

Diagnosis and underlying mechanism: common causes
In any circumstance in which the serum triglycerides exceed 11.0 mmol/L (1000 mg/dL), chylomicrons (in addition to VLDL) will be major contributors to the dyslipidaemia, even when the patient is fasting. This is because both chylomicrons and VLDL compete for the same clearance mechanism (lipoprotein lipase) in the circulation. This severe hypertriglyceridaemia (lipoprotein phenotype usually type V) tends to occur when an increase in hepatic VLDL production (either familial or secondary to, for example, obesity, diabetes, alcohol or oestrogen administration) is associated with decreased triglyceride clearance. This again may be genetic or acquired, for example, hypothyroidism, beta-blockade or diabetes mellitus (diabetes can cause both an overproduction of VLDL and decreased lipoprotein lipase activity). With the clearance mechanism already overloaded with VLDL, the rise in serum triglyceride levels, when chylomicrons enter the circulation following a fatty meal, may be tumultuous and they may spend days rather than hours in the circulation. The serum takes on the appearance of milk, and triglyceride levels may exceed 100 mmol/L (9000 mg/dL) (see Figure 10a). Thus, a patient, who might otherwise have a fasting serum triglyceride level of 5 mmol/L (450 mg/dL), can, with the injudicious use of alcohol or the development of diabetes, achieve extraordinarily high serum triglyceride levels.

What is the incidence?
Overall, the frequency of severe hypertriglyceridaemia (>11.0 mmol/L [>1000 mg/dL]) is probably no more than one in 1000 in adults and less in children.

Figure 9. Manifestations of severe hypertriglyceridaemia

Physical signs in severe hypertriglyceridaemia

• Tuberoeruptive xanthomata are characteristic of extreme hypertriglyceridaemia. These appear as yellow papules on the extensor surfaces of the arms and legs, buttocks and back (see Figure 10b).
• Often there is hepatosplenomegaly. Liver imaging shows the liver to be fatty, and bone marrow biopsy may reveal macrophages engorged with lipid droplets (foam cells). Because the triglyceride-rich lipoprotein may interfere with the determination of transaminases, giving spuriously high values, liver disease, in particular alcoholic liver disease, may be difficult to exclude, other than by the prompt resolution of the syndrome when a low-fat diet is instituted.
• Other features include lipaemia retinalis (pallor of the optic fundus, with both the retinal veins and arteries appearing white).

 

Complications of severe hypertriglyceridaemia

Atheroma risk Atheroma is not a complication of familial lipoprotein lipase deficiency, but it does complicate severe hypertriglyceridaemia in which there is lipoprotein lipase activity (albeit diminished). It is difficult to make a precise estimate of the risk from the dyslipidaemia per se because it is so frequently associated with insulin resistance or frank diabetes, which are also risk factors for atherosclerosis. If these are included as part of the syndrome, both CHD and peripheral arterial disease are common. The reason for the complete absence of lipoprotein lipase removing the risk of atheroma is not known with certainty, but it may be because the incidence of diabetes is not increased in familial lipoprotein lipase deficiency, because fibrinogen and factor VII activity are not increased, or because the conversion of VLDL and chylomicrons to the atherogenic LDL and remnant lipoproteins, respectively, is impaired in the absence of lipoprotein lipase. Acute pancreatitis Although atheroma is not directly owing to the high levels of triglyceride-rich lipoproteins, other complications are, for example, acute pancreatitis may occur when serum triglyceride levels exceed 20-30 mmol/L (2000-3000 mg/dL) (see above). The presentation of acute pancreatitis is similar to that from other causes. The diagnosis, however, may not be confirmed by detecting increased serum amylase activity, because falsely low values may be encountered because of interference by triglyceride-rich lipoproteins in the laboratory method. All laboratories should inspect serum for milkiness before reporting normal or only moderately raised serum amylase activity in patients with severe abdominal pain (see Figure 10b). Clinicians may otherwise wrongly exclude the diagnosis of acute pancreatitis, in favour of, for example, perforated peptic ulcer. Some patients do not develop acute pancreatitis, even when serum triglyceride levels exceed 100 mmol/L (9000 mg/dL). Others, who are more susceptible, experience recurring acute episodes. Chronic pancreatitis is not a feature of the condition. The pain tends to subside within a few hours or days of commencing nasogastric aspiration and intravenous fluids, with nothing taken by mouth. Occasionally, if such treatment is delayed, pancreatic pseudocysts may develop. In patients who are experiencing recurrent episodes of acute pancreatitis, usually because it has not proved possible to decrease their triglyceride levels adequately by dietary or pharmacological means, high-dose antioxidant therapy can dramatically decrease the attacks [Heaney, 1999]. Recurrent abdominal pain Recurrent abdominal pain (not typical of pancreatitis) sometimes occurs in patients prone to marked hypertriglyceridaemia, and may mimic irritable bowel syndrome. Severe abdominal pain may also sometimes be the result of splenic infarction. Pseudohyponatraemia Pseudohyponatraemia is another complication of extreme hypertriglyceridaemia, which may lead to serious consequences if unrecognised. Spuriously low serum sodium values are reported, because much of the volume of the serum aliquot on which the sodium measurement is made is occupied by lipoproteins as opposed to water. When the serum triglycerides exceed 40-50 mmol/L (3500-4500 mg/dL) the concentration of sodium in the aqueous phase (and thus the serum osmolality) may be normal, while spurious serum sodium levels of 120-130 mmol/L are being reported. The hazard is that these will be misinterpreted by the clinician, and a patient already seriously ill with pancreatitis, or occasionally, uncontrolled diabetes, will be made more ill by infusion of large volumes of isotonic saline or, worse, hypertonic saline. Focal neurological syndromes Focal neurological syndromes, such as hemiparesis, memory loss and loss of mental concentration, may complicate extreme hypertriglyceridaemia, perhaps because of ischaemia owing to sluggish microcirculation caused by the high concentrations of chylomicrons in the blood. Paraesthesiae, especially in the feet, may also be an occasional feature, even in the absence of diabetes. Rheumatological manifestations Sicca syndrome and polyarthritis have also been described, but undoubtedly the most common articular association is gout (see later).

What is the lipoprotein phenotype?
Raised fasting serum triglyceride levels in the range 2-10 mmol/L (200-900 mg/dL) in the absence of a cholesterol level exceeding 5 mmol/L (200 mg/dL) are occasionally discovered, indicating type IV hyperlipoproteinaemia.

Occurrence
Diabetes and an excess of alcohol are important causes of this hypertriglyceridaemia, although it is sometimes present in a fit, non-obese person with none of these factors. Family studies may then reveal similar increases in relatives, in which case the condition is called familial as opposed to sporadic hypertriglyceridaemia. Epidemiological studies show that the triglyceride level is associated with an increased risk of CHD, although how frequently this is the case when cholesterol levels are less than 5 mmol/L (<200 mg/dL) is hard to know. The association is linked inseparably with low levels of HDL and with impaired glucose intolerance.

 

When to treat?

Undoubtedly, patients with established CHD and hypertriglyceridaemia whose serum cholesterol does not exceed 5.0 mmol/L (200 mg/dL) do exist. These patients generally have low levels of HDL-C and perhaps also an increased level of cholesterol-depleted, small dense LDL, which is not evident from their cholesterol level (see earlier). Such patients are likely to benefit from lipid-lowering therapy and they also have a greatly increased risk of developing diabetes mellitus over the next few years. Hypertriglyceridaemia increases the risk of any associated increase in serum cholesterol, but in the absence of hypercholesterolaemia there is inadequate evidence to favour its treatment as a means of primary prevention of CHD. Occasionally, triglyceride levels of 5.0 mmol/L (450 mg/dL) or less must be treated, if they occur in patients prone to periodic exacerbations of more severe hypertriglyceridaemia associated with acute pancreatitis. Generally, levels exceeding 10 mmol/L (900 mg/dL) justify therapy, but clinical judgement must be used for levels of 5-10 mmol/L (450-900 mg/dL). In diabetes, evidence that serum triglycerides are an independent risk factor for CHD justifies, in the view of some authorities, specific lipid-lowering therapy at lower levels than in patients without diabetes, after improvements in diet and glycaemic control have been exhausted as a means of decreasing triglyceride levels.