Eruptive Xanthomas
Abnormal
accumulation of triglycerides in various tissues, including the skin, may lead
to the cutaneous finding of eruptive xanthomas. The xanthomatous diseases are a
diverse group of conditions with unique clinical, laboratory, and systemic
findings. An abnormality in lipid and cholesterol metabolism is what links
these conditions together. Fatty acids provide the body with more than 40% of
its daily energy requirements. The majority of fatty acids are supplied
directly by the normal diet. Proteins and carbohydrates, when present in
excess, can be converted to triglycerides to be stored as a future energy
source. This process makes up the remaining source of free fatty acids and
triglycerides supplied to the body.
Normal metabolism of triglycerides
occurs through complex biochemical pathways. Triglycerides are converted into
free fatty acids, which are broken down into acetyl-coenzyme A (acetyl-CoA).
Acetyl-CoA then enters the Krebs cycle to be oxidized and turned into adenosine
triphosphate (ATP), one of the main forms of energy used in cellular processes.
Ingested triglycerides are broken
down into free fatty acids in the lumen of the intestine by bile acids. The
free fatty acids are then transported across the gut lining as chylomicrons.
This process is very rapid and occurs within 6 hours after eating. The
chylomicrons are absorbed by many tissues and are converted back into free
fatty acids and glycerol by the enzyme lipo- protein lipase. The free fatty
acids can be converted to acetyl-CoA, converted to triglyceride and stored as
an energy source for later use, or used to make various phospholipids. The
storage of triglycerides for future energy use is ideal, because it yields
higher amounts of energy than either proteins or carbohydrates. Triglycerides
can yield 9 kcal/g of energy, whereas proteins and carbohydrates produce about
4 kcal/g. This is an efficient means of storing energy. Abnormalities in the
production, breakdown, or storage of triglycerides may lead to complications
resulting in cutaneous and systemic findings.
Eruptive xanthomas are one of the
cutaneous findings caused by an abnormality in lipid metabolism. They can be
caused by various familial hyperlipoproteinemias (types I, III, and V), by
medications, or as a complication of diabetes. The cutaneous findings are
identical in all of these conditions. Eruptive xanthomas should not be confused
with tuberoeruptive, tendinous, or planar xanthomas, because these conditions
have different biochemical bases and other systemic features that are unique.
Treatment of eruptive xanthomas requires a team approach including
endocrinology, car- diology, and dermatology specialists.
Clinical Findings: Eruptive xanthomas, as the name implies, have a
rapid eruptive onset (hours to a few days). The most common location to be
involved is the buttocks, but these eruptions can be seen anywhere on the body,
including the mucous membranes. They have a predilection for the extensor
surfaces of the skin.
They appear as yellow to slightly
red-orange, domeshaped papules with an erythematous base. Patients often
complain of mild pruritus, but occasionally they describe a painful sensation
when the lesions are palpated. Eruptive xanthomas are rare in both children and
adults, but they are more commonly seen in adulthood. There are no racial or
sexual differences in incidence.
Patients diagnosed with eruptive
xanthomas that are found to be caused by a deficiency in the enzyme lipoprotein
lipase are classified as having type I hyperlipoproteinemia. This is a rare
form of hyperlipoproteinemia with onset in childhood. Systemic involvement is
significant, with recurrent bouts of pancreatitis and hepatosplenomegaly. These
patients have extremely elevated triglyceride and chylomicron levels but normal
cholesterol levels. The eye may also be affected with lipemia retinalis.
Lipemia retinalis can be seen only by means of a funduscopic examination.
Vision is typically normal, and the patient is unaware of any eye
abnormalities. The blood vessels within the eye have a creamy white color
because of the excess lipid in the blood-stream. The arteries and veins are
equally affected, and the only way to differentiate the two is by comparing the
caliber of the vessel. The arterial light reflex is lost. The vessels appear
flat, and the rest of the fundus is a uniform creamy color. Lipoprotein lipase
enzyme activity can be measured, and this test is used to help diagnosis type I
hyperlipoproteinemia. Eruptive xanthomas can also be seen as part of
hyperlipoproteinemia type III (familial dysbetalipoproteinemia) and
hyperlipoproteinemia type V. Type III has been found to be caused by a defect
in the APOE gene, which encodes the apolipoprotein E protein. This
protein is particularly important in clearing chylomicrons and
intermediatedensity lipoproteins.
Multiple medications have been
implicated in the production of hypertriglyceridemia. They include
isotretinoin, glucocorticoids, olanzapine, protease inhibitors (especially
ritonavir), and indomethacin. Alcohol abuse can also be a cause of
hypertriglyceridemia. Patients presenting with eruptive xanthomas who are
taking any of these medications should have the medication discontinued or
another substituted and should be reevaluated after treatment.
Diabetes is the most common cause
of hypertriglyceridemia, and it probably is also the most common cause of
eruptive xanthomas. Insulin is required for normal functioning of the
lipoprotein lipase enzyme. Diabetic patients who are deficient in insulin have
lower activity levels of lipoprotein lipase and increased levels of
chylomicrons and triglycerides as a result.
On laboratory evaluation, the
patient has triglyceride levels that are extremely elevated, in the range of
2000 mg/dL sometimes even surpassing the laboratory’s ability to quantify it.
If a sample of blood is centrifuged for a few minutes, the white to
creamycolored triglycerides will become evident and will take up a considerable
amount of the specimen. On occasion, there are so many triglycerides present
that the blood sample is a light creamy color even before centrifugation.
Histology: The histological findings from biopsies of
early lesions of eruptive xanthomas can mimic those of granuloma annulare.
Neutrophils can be evident during the formation of an eruptive xanthoma. The
neutrophilic infiltrate lessens and disappears once the lesion has had time to
establish itself. It is recommended that the biopsy specimen be taken from an
established lesion (one that has been present for a day or two) so that more
characteristic findings will be seen. Foam cells are present with a stippled
cytoplasm. The number of foam cells is not as prominent as in tuberous or
tendinous xanthomas. One unique finding is the presence of extracellular lipid,
which is seen between bundles of collagen.
Pathogenesis: The varying conditions that can manifest with
eruptive xanthomas all have unique ways of causing hypertriglyceridemia.
The final common pathway in the pathogenesis of eruptive xanthomas is the
presence of significantly elevated triglyceride levels. Treatment: The
main goal of therapy is to return the triglyceride level back to a normal
range. Medications that can cause hypertriglyceridemia need to be discontinued.
Underlying diabetes needs to be treated aggressively to get better control of
glucose metabolism and insulin requirements. Those patients with
familial causes need to institute dietary changes (to avoid medium-chain
triglycerides), increase their activity level, and take triglyceride-lowering
medications. These medications can be used for all causes of
hypertriglyceridemia. The medications most commonly used to low r triglyceride
levels are fenofibrate and gemfibrozil.
