Are You Confident of the Diagnosis?
What you should be alert for in the history
Slowly growing and sometimes subtle the tendon xanthoma presents as a firm-to-hard subcutaneous nodule with normal overlying skin. The sites of predilection are the Achilles tendons and extensor tendons of the digits. They can be associated with periosteal xanthomas that occur on the ankle malleoli, tibial tuberosity, and olecranon process.
Small tendon xanthomas are asymptomatic and slow growing and many develop over decades. Patients can be unaware of their presence and some lesions become apparent only by palpation or radiographic study.
The most common cause of tendon xanthoma is heterozygous familial hypercholesterolemia. These patients have elevated plasma levels of low density lipoprotein (LDL), as well as cholesterol, throughout their lives but do not develop symptomatic atherosclerotic disease until adulthood.
Individuals with homozygous familial hypercholesterolemia have substantially higher elevations of LDL than heterozygotes. Their elevated plasma LDL levels also predispose them to the development of tendon xanthomas. However, they often succumb to atherosclerotic disease before tendon xanthomas can develop.
Massive tendon xanthomas can develop in two rare disorders characterized by the accumulation of unusual sterols transported by LDL. In cerebrotendinous xanthomatosis, a disorder of bile acid metabolism, cholestanol is the elevated sterol. In b-sitosterolemia, plant sterols like sitoserol, campesterol, and stigmasterol are elevated due to excessive intestinal absorption.
Characteristic findings on physical examination
On physical examination, tendon xanthomas manifest as firm-to-hard subcutaneous nodules with normal overlying skin (Figure 1). They are typically found over the Achilles tendons and extensor tendons of the hand.
Expected results of diagnostic studies
The hallmark histopathologic feature of all xanthomas is the presence of foam cells within the dermis. These cells represent macrophages, which contain lipid. These cells will stain positive for lipid with special stains (Oil-red-O). Furthermore, tendon xanthomas (and tuberous xanthomas) are unique in that they possess cholesterol clefts. These collections of cholesterol esters stain positive with a special stain (Schultz stain) and are doubly refractile.
Patients with tendon xanthomas should have a fasting lipid profile performed. Since familial heterozygous hypercholesterolemia is the most common entity associated with tendon xanthomas, an elevated LDL will be the most commonly encountered abnormality.
The level of LDL elevation can be utilized to distinguish the heterozygous vs. homozygous forms of familial hypercholesterolemia. Heterozygotes will have LDL levels approximately twice the normal value. Homozygotes will have LDL levels elevated to the range of 800-1,000mg/dl. If a rare etiology of a tendon xanthoma is suspected, levels of cholestanol and sitosterols can be used to identify patients with cerebrotendinous xanthoma and b-sitosterolemia, respectively.
The morphology of the tendon xanthoma, a firm-to-hard subcutaneous nodule on a tendon and near a joint, creates a differential diagnosis that includes all kinds of benign and malignant tumors. The typical bilateral nature of tendon xanthomas is an important feature in their recognition.
Who is at Risk for Developing this Disease?
The most clinically significant entities associated with the development of tendon xanthomas are familial heterozygous and homozygous hypercholesterolemia. The heterozygous form is by far more common with approximately one in 500 individuals affected. The incidence of the homozygous form of familial hypercholesterolemia has a prevalence of one individual in 1 million.
Recognition of the association between tendon xanthoma and familial hypercholesterolemia is critical as these individuals are at a substantially elevated risk of developing atherosclerotic disease. Since the level of elevation of LDL in the heterozygous form is not as great, these individuals have less severe progression of their atherosclerotic disease and can survive into adulthood.
Persons with homozygous familial hypercholesterolemia typically have such high elevations of their LDL levels (up to 1,000mg/dl) that they develop and succumb to atherosclerotic disease in their youth. It is less likely that homozygous familial hypercholesterolemia patients will present with a tendon xanthoma as the cutaneous lesions take decades to form.
Patients with homozygous familial hypercholesterolemia can be recognized by another, pathognomonic type of xanthoma, the intertriginous xanthoma. These planar xanthomas manifest as slightly raised yellow plaques, often with a cobblestone surface appearance. They are characteristically seen in the finger webspaces, but may occur in the axillae and antecubital and popliteal fossae.
What is the Cause of the Disease?
Tendon xanthomas occur in the setting of elevated low density lipoprotein. The elevation of LDL can be either as a primary elevation of cholesterol (in the familial hypercholesterolemia syndrome) or in conjunction with elevation of cholestanol or sitosterols.
There is good evidence that the lipid found within xanthomas is the same lipid circulating in high concentrations in the plasma of patients. However, the exact mechanisms that induce xanthoma formation are less clear. It has been demonstrated that using scavenger receptors for LDL macrophages can take-up lipid and become transformed into foam cells.
It has also been shown that extravasated lipid can attract foam cells through modulation of vascular endothelial receptors. Furthermore, oxidized low density lipoprotein has been shown to induce the formation and infiltration of foam cells within the dermis.
The steps of cholesterol metabolism relevant to the formation of tendon xanthomas begin with the formation of the very low density lipoprotein (VLDL) by the liver. These are triglyceride-rich molecules similar to chylomicrons; however, they contain relatively more cholesterol. The VLDL molecule contains apolipoprotein-100 as its predominant apolipoprotein.
Similar to the chylomicron, once the VLDL leaves the liver it travels through the peripheral circulation where lipoprotein lipase acts upon its triglyceride elements. As triglyceride is removed from the VLDL a residual particle, the VLDL remnant, continues to travel through the circulation.
VLDL remnants are removed from the circulation by the interaction of apolipoprotein-E, and apolipoprotein-100 with receptors on hepatocytes. Upon recognition of the apolipoproteins by receptors on hepatocytes, the VLDL remnant is internalized. Many of the VLDL particles are degraded within hepatocytes to their constituent lipids; however, a portion of these particles interact with hepatic lipase, which removes the residual triglyceride and converts the VLDL to LDL.
LDL particles transport most of the cholesterol present in the fasting serum. They are associated with only one lipoprotein, apolipoprotein-100. Apolipoprotein-100 is recognized by the LDL-receptor. Three-fourths of LDL is removed from the circulation by LDL-receptors on hepatocytes. The remaining fraction is removed by peripheral tissues via non-receptor mediated pathways.
Individuals with familial hypercholesterolemia lack functioning LDL receptors. Patients afflicted with the most severe, homozygous form, lack functioning LDL receptors. Therefore their plasma levels of LDL are elevated to the most striking levels. Heterozygotes have one functioning allele and therefore their LDL levels aren’t as severely elevated.
Local factors like heat, movement, and friction may increase LDL leakage from capillaries. These local effects are thought to explain the sites of predilection for the formation of tendon xanthomas.
Systemic Implications and Complications
Recognition of tendon xanthomas should prompt the clinician to consider the consequences of elevated LDL on the patient’s coronary and systemic vasculature. These patients should be screened for lipid abnormalities and have aggressive treatment of their lipid abnormalities to slow the progression of atherosclerotic disease.
Lifestyle modifications and prevention
Dietary modification (only modestly helpful)
HMG CoA reductase inhibitors (statins)
Bile acid sequestrants
Surgical treatments for familial hypercholesterolemia
Liver transplantation (in homozygous familial hypercholesterolemia)
Physical modalities to reduce circulating LDL
Surgical treatments for tendon xanthoma
Surgical removal of large xanthoma causing tendon or joint instability
Optimal Therapeutic Approach for this Disease
Dietary modifications to reduce the amount of cholesterol consumed are a reasonable addition to the treatment plan of patient with tendon xanthomas. However, since the pathophysiology surrounds improper clearance of circulating LDL the addition of a systemic treatment is necessary in most cases.
In patients with heterozygous familial hypercholesterolemia (the majority of patients with tendon xanthoma), treatment with an HMG-CoA reductase inhibitor (statin) is effective in decreasing the size of xanthomas. These medications are most effective in heterozygotes, as they have been shown to up-regulate their ’non-mutant’ LDL receptor allele. To achieve normalization of plasma lipid levels in patients with heterozygous familial hypercholesterolemia, additional medications like bile acid binding resins or ezetemibe may be needed.
While following a patient on a statin, clinicians should be aware of two significant adverse events: myopathy and hepatotoxicity, which can be exacerbated by the addition of other medications (cyclosporine, systemic antifungals, and fibric acid derivatives).
In patients with the homozygous form of familial hypercholesterolemia, high dose statins can cause a moderate reduction in LDL. It is felt that this is through inhibition of VLDL secretion in contrast to the mechanism of action in heterozygous patients.
Surgical and physical treatments to reduce LDL
The patient with homozygous familial hypercholesterolemia will often need a more radical treatment approach including physical modalities like LDL apheresis and in some cases liver transplantation. Through periodic apheresis, LDL is removed from the patient’s plasma. In rare cases, liver transplantation has been utilized to treat homozygous familial hypercholesterolemia. The donor liver provides the patient with functioning LDL receptors, which clear the high levels of circulating LDL.
Surgical treatments for tendon xanthomas
Typically tendon xanthomas do not cause symptoms. However, if they become large enough they can cause joint and tendon instability. At this point patients should be referred for surgical management of their xanthoma.
Tendon xanthomas change in size very slowly and can be expected to diminish in size very slowly once the patient is treated. They very rarely cause morbidity but can cause tenosynovitis or symptoms of mechanical instability.
By recognizing this cutaneous manifestation of hyperlipidemia, patients at high risk of atherosclerotic disease can be identified and treated with cholesterol lowering medications. These patients will need regular and consistent monitoring of their lipid levels and they should be managed in combination with their primary care physician and cardiologist.
There are hereditary implications to making the diagnosis of either heterozygous or homozygous familial hypercholesterolemia. Identification of an individual with familial hypercholesterolemia should prompt screening of first-degree relatives with age-appropriate lipid studies and a referral to medical genetics should be made, if available.
Unusual Clinical Scenarios to Consider in Patient Management
Familial defective apo-B100 is another disease that can induce the formation of tendon xanthomas. These patients have an apo-B100 that is unable to bind to the LDL receptor properly. Similar to familial hypercholesterolemia, this entity has both a homozygous and a heterozygous disease state. Homozygous individuals are rarely encountered, but have higher LDL levels than heterozygotes. Overall, these individuals will have LDL levels that are lower than familial hypercholesterolemia patients. These patients are at an increased risk of atherosclerotic disease and respond well to statin therapy.
Other rare entities associated with the development of tendon xanthomas include conditions that induce elevation of cholestanol (cerebrotendinous xanthomatosis), plant sterols (sitosterolemia), overproduction of apo-B, familial dysbetalipoproteinemia, dysglobulinemias, and hepatic cholestasis. Tendon xanthomas have also been reported in persons with normal lipids.
What is the Evidence?
Cruz, PD, East, C, Bergstresser, PR. “Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders”. J Am Acad Dermatol. vol. 19. 1988. pp. 95-111. (A review of the dermatologic manifestations of the various types of xanthomas is presented.)
Elder, DE. “Lever’s Histopathology of the Skin”. 2005. (The salient histologic features of eruptive xanthomas are reviewed.)
Kasper, DL. “Harrison’s Principles of Internal Medicine”. 2005. (This reference provides a complete review of lipoprotein metabolism.)
Goodman, LS. “Goodman and Gilman’s pharmacological basis of therapeutics”. 2011. (The therapeutic principles of the treatment of hyperlipidemia are reviewed, as well as dosing regimens.)
Uauy, R, Zwiener, RJ, Phillips, MJ, Petruska, ML, Bilheimer, DW. “Treatment of children with homozygous familial hypercholesterolemia: safety and efficacy of low-density lipoprotein apheresis”. J Pediatr. vol. 120. 1992. pp. 892-8. (In extreme circumstances apheresis has been attempted to treat patients with homozygous familial hypercholesterolemia.)
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.