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ABSTRACT 
Familial hypercholesterolemia is a common autosomal dominant condition characterised by increased low density lipoprotein cholesterol, tendon xanthomas and premature atherosclerosis. Ultrasonography is the diagnostic tool of choice for the detection of tendon xanthomas in the Achilles tendon, demonstrated by the presence of hypoechoeic nodules or an increase in the antero-posterior diameter. It can also be used in screening and clinical follow-up of patients with familial hypercholesterolemia.
Keywords: tendon xanthoma, familial hypercholesterolemia, ultrasonography
 
INTRODUCTION 
Tendon Xanthoma (TX) is a hallmark of familial hypercholesterolemia (FH), a common autosomal dominant disorder affecting 1 in 500 persons in the US in its heterogeneous state (hFH)(1). This derangement in lipid metabolism can be screened and diagnosed by the triad of TX, type 2A hypercholesterolemia and a personal or family history of premature atherosclerosis.
This group of patients are at risk of premature atherosclerosis and myocardial infarction due to raised LDL-cholesterol. FH meets the WHO criteria for a worthwhile screening programme, which include the ability to detect the condition in the pre-clinical phase, the existence of an accurate, acceptable test, and an accepted and effective treatment(1) . There is a case to be made in trying to diagnose such patients early and getting them treated to lower their lipid levels and hence their risk for myocardial infarction. 
We report a family of heterozygous familial hypercholesterolemia whose diagnosis was alerted by the tuberous xanthomas around the elbows and enlarged Achilles tendons in the index case. These clinical features prompted us to examine her for a lipid disorder and upon confirmation of that to screen the family members.

CASE REPORT 
Miss CLQ, a 26-year-old Chinese, was noted to have nodular swellings over both her elbows in the course of a consultation for acute gastroenteritis. The swellings were painless and had been present for a few years. She did not have any significant past history. Her paternal grandfather and uncle died at the age of 48 years and 55 years respectively from acute myocardial infarction.
Clinically, she had tuberous xanthomas over the extensor surface of both elbows and left knee and thickened Achilles tendons. No xanthelesma or arcus cornea was detected. Her blood pressure and weight were normal (BMI = 23). No abnormality was detected upon auscultation of her heart and examination of her peripheral pulses.
Clinical and ultrasonography studies were done on her first degree relatives viz an elder brother, a younger sister and her parents. Except for her mother who had a normal lipid profile, type 2A hyperlipidemia was documented in the rest of the family (Table I). 
Their Achilles tendons were studied and the clinical and sonographic features are shown in Table II. The antero-posterior (A-P) diameter of the patient's Achilles tendons, were surprisingly within the normal limits despite the clinical impression that they were enlarged. Her father's Achilles tendons were visibly irregular and thickened with significant increase in the A-P measurements on ultrasonography (Fig 1). Ultrasonography performed for her brother showed borderline thickening of the left Achilles tendon with an anterior hypoechoic region that was consistent with xanthomatous involvement of the tendon. Her younger sister had hypoechoic nodules in both her Achilles tendons (Fig 2). Her right tendon was thickened and sonographic signs of tenosynovitis were present. The thickening persisted after the signs of tenosynovitis resolved two months later.
Tuberous xanthomas on extensor aspects of both elbows of the patient were confirmed by ultrasonography (Fig 3). These deposits were found to be located in the subcutaneous tissue, superficial to the extensor tendons.
The presence of the triad of Type IIa hyperlipidemia, TX and a positive family history of premature artherosclerosis supported the clinical diagnosis of hFH in the patient, her two siblings and her father.

DISCUSSION 
Tendon xanthomas (TX), in familial hypercholesterolemia (FH), are due to deposition of lipid-laden macrophages within the tendon fibrils and not on the tendon sheath(2). The Achilles tendon, extensor tendons of the fingers and patellar tendons are common sites for development of xanthomas. Predilection for these areas may be the result of constant stretching, pressure and trauma. They have also been reported in the plantar aponeurosis, the fascia and periosteum overlying the lower tibia and the peroneal tendons. Besides TX, patients with FH also manifest xanthelesma, arcus cornea and tuberous xanthomas.
The presence of TX is virtually pathognomonic of familial hypercholesterolemia(3). TX, however, also occur in two rare conditions, cerebrotendinous xanthomatosis and sitosterolemia, which have their own distinct clinical and biochemical features, and are not easily confused with FH.
In 1986, Vega and Grundy first noted a defect in LDL itself rather than the number of functional LDL receptors residing on the liver cells (as is the case in FH) while studying patients with moderate hypercholesterolemia(4). The defect was isolated to a defective binding of the ligand apolipoprotein B100 to the LDL receptor, and the condition was termed familial defective apolipoprotein B100 (FDB). FH and FDB both result from defects in the LDL receptor pathway, and therefore present with similar clinical features of Type IIa hyperlipidemia, TX and a family history of premature atherosclerosis. Hence, sophisticated laboratory techniques such as cultured fibroblasts and DNA studies, which are available only in specialist research centres, are needed to tell them apart. 
As we are unable to perform these tests on our patients, we therefore cannot exclude FDB with absolute certainty. However, FDB, which is also an autosomal dominant monogenic disorder, is less common. Amongst patients in European studies diagnosed to have FH using classical criteria, only 4% to 6% were later found to have FDB(5). Also, FDB may exist only in Caucasians. In Japan, Nohara et al using PCR assay were unable to detect any case of FDB in 385 Japanese patients known to have FH(6). Haplotype analysis suggest that the gene mutations that lead to FDB are derived from a single common ancestral mutation that occured probably in a Caucasian 10,000 years ago. 
The clinical significance of differentiating FH and FDB is that the latter has a poorer response to drugs acting on LDL receptors(7). This fact is important in the search for new drugs tailored to address the defect in ligand apoprotein B100. Until such drugs are available, the clinical management of both FH and FDB remains the same. 
TX are detected by clinical examination in only 70% of persons with FH after the age of 20(8). The thickening of the tendon may only be antero-posteriorly and difficult to assess clinically. Further, 50% of the tendons have homogenous thickening and do not produce circumscribed tendon morphology that can be detected by inspection or palpation(9, 10). Rolling the tendon between the fingers to detect surface irregularity(11) and observing for the loss of posterior curvature of the Achilles tendons(12) are clinical techniques that may add to the sensitivity of detection. 
The thickness of the Achilles tendon is a generally accepted clinical marker for TX. It is accessible to measurement, correlates with the severity of the coronary artery involvement and can be used to monitor progress in cholesterol lowering therapy(10). Mabuchi et al in 1977, using plain radiographic techniques, established that the Achilles tendon thickness in patient with FH, with or without clinically apparent TX was significantly greater than those found in secondary hypercholesterolemia from hypothyroidism and nephrotic syndrome(13). The thickness of the tendon in patients with FH was also found to increase with age.
Historically, xeroradiography was the preferred radiographic technique for measurement of the A-P thickness of the Achilles tendon. Xeroradiography, introduced by Xerox in 1952, is a complex electrostatic process based on a special material called a photoconductor. This system uses edge enhancement for better delineation of the margin of low contrast objects. The cost of the xeroradiographic system and its limited usage has contributed to its decline in its use.
Ultrasonography is now the imaging tool of choice in the work-up of patients with FH and in the evaluation of treatment efficacy. It does not entail exposure to radiation as in conventional X-ray and computed tomography. Its clinical efficacy has been compared with Magnetic Resonance Imaging (MRI). Ultrasonography with high resolution linear-array equipment has been rated superior to MRI in the evaluation of xanthomatous lesions by Bude et al(14). The extent of focal intra-tendinous xanthoma is not demonstrated by MRI, although xanthomatous deposits produce characteristic speckled or reticulated MRI appearance.
Recent improvements in the state-of-the-art, high frequency, linear-array transducers have enabled much better definition of internal tendon structure, which resulted in the improved visualisation of TX, compared with that reported previously. It is possible for sonography to detect xanthomas in tendons that are normal or questionably enlarged by palpation(12). The sonographic appearances of the xanthomatous Achilles tendon include the presence of hypoechoic lesions and tendon enlargement(12). Tendon enlargement is considered present if the maximum AP diameter of the tendon exceeded 2 standard deviations from the mean. The upper limits have been established by Steinmetz et al(10) for Caucasians and by Yuzawa et al(9) for Japanese subjects. We used Yuzawa 's figures of 5.1 mm for males and 4.8 mm for females in our patients who are Chinese.
It is interesting to note that the patient's sister gave a history of intermittent pain over the Achilles tendon for a few years. Ultrasonography of her Achilles tendons revealed features of tendinitis. Glueck et al reported an association of tendinitis with FH and that pain in the Achilles tendons may be a presenting symptom in FH(15). Thc symptoms of Achilles tendinitis were often attributed to gout, pseudogout or trauma and the possibility of an underlying lipid disorder is often overlooked. There is a place for blood cholesterol screening for patients who present with recurring Achilles tendinitis and tenosynovitis which cannot be explained after excluding gout and trauma. However, it should be noted that entities other than xanthoma can appear as focal or diffuse hypoechoic lesions in tendons, including diffuse or focal tendinitis, partial tears, and rarely, infection.
hFH can be identified during routine blood cholesterol screening done in the clinic or when the patient presents with cardiovascular disease. The National Cholesterol Education Programme (NCEP) has recommended that all persons above 20 years of age should have their blood cholesterol checked and if there are evidence to suspect a genetic  disorder,  their  first  degree  relatives  should  also be  screened(16).   It   is   important   to   exclude   other  forms of hypercholesterolemia such as secondary hypercholesterolemia and polygenic hypercholesterolemia in the approach to a patient with hypercholesterolemia. The presence of TX in patients or their first degree relative is crucial for the diagnosis of FH. Hence ultrasonography will be a useful screening tool as it can detect the presence of xanthomas which are clinically not palpable.
With the advent of effective and better tolerated cholesterol-lowering drugs, early detection and treatment assume even greater significance. Ultrasonography could be used to monitor regression because TX may shrink with lipid lowering therapy(17). Clinical and limited imaging studies have suggested that a positive correlation exists between tendon xanthoma regression and improvement in atherosclerotic disease in patients with FH who are undergoing lipid-lowering therapy(18).
Despite the benefits of screening and treating FH, a study by Cheong et al(19) revealed that important facts on TX are not known to many doctors and inadequately documented in many text books. In a questionnaire given to 60 Family Medicine postgraduate trainees, it was found that only 40% of these doctors knew of the unique association of TX with FH, a similar number knew of the intra-tendinous nature of xanthomatous deposits while only 16% were aware of the usefulness of ultrasonography. In comparison, 74%, 23% and 3% respectively of 72 medical text books documented these facts. These 72 general internal medicine and dermatology books were selected from the reference collection of 170 books on these subjects in the National University of Singapore Medical Library on the basis that either TX, FH or primary hyperlipidemia was listed in their index. 

CONCLUSION 
Being alert to the presence of tendon xanthoma in a patient with hypercholesterolemia helps in the identification of familial hypercholesterolemia. There is a need for us to be vigilant to identify these cases as treatment of the lipid disorder will lower the risk of myocardial infarction. We need to remind ourselves of the clinical features and the relationship of these to familial hyperlipidemia.
Our case study also illustrates the importance of family screening in the primary care setting. This is particularly important in familial hypercholesterolemia as it is an autosomal dominant condition. Identification of individuals with familial hypercholesterolemia may improve with awareness of the use of ultrasonography as an imaging tool for the detection of tendon xanthoma. 
Ultrasonography is useful not only in diagnosis but also for monitoring the progress of the condition to lipid lowering treatment.