The Journal of the American Dental Association
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J Am Dent Assoc, Vol 139, No 2, 152-157.
© 2008 American Dental Association
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CLINICAL PRACTICE

Drug-induced paraparotid fat deposition in patients with HIV

Case reports



Louis Mandel, DDS and David Alfi, DDS


   ABSTRACT
TOP
 ABSTRACT
CASE REPORTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background. The treatment of patients with HIV is managed effectively with highly active antiretroviral therapy, but complications in the form of a lipodystrophy syndrome (LDS) often develop.

Case Descriptions. The authors describe two patients who had bilateral parotid area fatty swellings, which are a manifestation of the fat redistribution seen in LDS. Fat hypertrophy, fat atrophy or both in other regions; dyslipidemia; and glucose abnormalities also were present.

Conclusion and Clinical Implications. Although the LDS in patients with HIV is recognized visibly by fat redistribution, the syndrome includes dyslipidemia and insulin resistance. Dental visits give dentists the opportunity to recognize HIV-related cervicofacial fat alterations. For appropriate attention, referral to the patient’s physician who is managing the HIV is indicated.

Key Words: Paraparotid fat; lipodystrophy; lipodystrophy syndrome; highly active antiretroviral therapy

Abbreviations: CT: Computed tomography. • DILS: Diffuse infiltrative CD8 lymphocytosis syndrome. • HAART: Highly active antiretroviral therapy. • LD: Lipodystrophy. • LDS: Lipodystrophy syndrome. • NRTI: Nucleoside reverse transcriptase inhibitor. • PI: Protease inhibitor. • SGC: Salivary Gland Center.

Since highly active anti-retroviral therapy (HAART) began being used to treat patients infected with HIV, the disease has morphed into a chronic manageable condition. The successful HAART regimen, introduced 12 years ago, usually includes two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) or a non-NRTI. As a consequence of using these medications, patients have experienced collateral damage in the form of metabolic disorders, and the health care profession is recognizing these disorders.

Early reports in the literature1,2 noted the occurrence of lipodystrophy syndrome (LDS) with HAART. This syndrome is defined as significant body fat redistribution, dyslipidemia and insulin resistance. The body fat redistribution, or lipodystrophy (LD), manifests itself in different body regions as a fatty hypertrophy, fatty atrophy or both. An accumulation of central fat and changes in subcutaneous fat deposits usually occur at the same time, but they can develop separately.3–5 Increased fat deposition occurs in abdominal viscera with or without increased subcutaneous fat and results in increased waist circumference.3,5–8 Dorscocervical fat depositions are noted with the development of a buffalo hump and thickening of the neck.5–10 Breast enlargement from fat deposits also has been described.5,9 Conversely, fatty atrophy with wasting is seen in the face, buttocks and extremities.4–8,10

LDS in patients with HIV who are receiving HAART also involves dyslipidemia with elevated cholesterol and triglyceride levels,2,5,7,9,11,12 and it affects 60 percent of these patients.5,13 It generally is believed that the PIs are responsible for the hyperlipidemia.3,5,13–15 The effect of the PIs on dyslipidemia, however, varies among PI medications, and it is not limited only to the use of PIs.

The third component of LDS is insulin resistance—a decreased sensitivity to insulin demonstrated by insulin-targeted tissues. Insulin resistance and impaired glucose tolerance have been reported in relation to PIs,1,16 but the mechanism for this development is not known. Diabetes mellitus has been observed in 7 percent of patients taking a PI, and another 16 percent of patients had abnormalities in glucose tolerance.5,17

An increase in cardiovascular disease in patients with LDS and HIV who are receiving HAART has been reported.5 After eliminating known risk factors, researchers saw a 16 percent increase in cardiac events annually in patients who received HAART; they found that PIs were associated with this increase.5 Although HIV may be a factor in atherosclerosis, antiretroviral agents’ effect on lipids and insulin sensitivity contributes to its premature development.5

There is a generally higher prevalence of patients with LDS associated with long-term HAART. LDS has been reported to develop in 20 to 84 percent of patients after they have received HAART for two or more years.2,5,7,8,18,19 Both PIs and non-PI antiretroviral drugs are considered to be contributory to LDS.7 Older patients18 and those with longer durations of HIV infection7 have an increased risk of developing LDS. In women, LDS incidence ranges from 10.5 to 37.0 percent, but it probably is underreported.7 With continued use of HAART and longer follow-up periods, increases in the occurrence of LDS should be anticipated.

NRTIs, particularly stavudine, are thought to be responsible for the lipoatrophy seen in these patients through their toxic effect on mitochondria.5,6,20,21 Mitochondrial dysfunction and depletion bring about an increase in lipolysis and adipose cell apoptosis.3,5,7,11,14,18,22 The newer NRTIs, abacavir and tenofovir, have not been implicated in the occurrence of fat atrophy.5 The NRTI fat loss is accelerated when most PIs are added to the drug regimen,5,7,11,23 but PIs alone have been reported to cause lipoatrophy in 64 percent of patients2 by impairing adipose cell differentiation.5

Reports have suggested that PIs also are associated with visceral fat accumulation,11,24,25 which may be an indirect effect of subcutaneous fat wasting with the visceral depots providing alternative sites for storage of fat lost in the peripheral areas.11 However, the exact pathophysiology for increased fat deposition has not been determined, and it may represent an improved physical state resulting from the decreased viral load.5

In this article, we present case reports of two patients with no previously reported paraparotid fat deposition. We focus on the clinical symptomatology of LD, which is a clinically visible sign of LDS.


   CASE REPORTS
TOP
 ABSTRACT
 CASE REPORTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Case 1. A 46-year-old man’s HIV was diagnosed eight years before we examined him. He did not recall all of the medications he received initially, but he was certain that it included the NRTI stavudine. He reported that for the past five years he had received HAART that included efavirenz, emtricitabine and tenofovir, which are a non-NRTI and two synthetic nucleosides, respectively. The patient said he was currently receiving simvastatin and bupropion.

Four years before we examined him, the patient became aware of painless persistent swellings in both parotid areas (Figure 1Go). These swellings slowly increased in size, and the patient became concerned about his facial appearance, which led him to seek medical attention. Laboratory studies revealed that he had a high fasting glucose level (117 milligrams per deciliter; normal 65–95 mg/dL) and a high triglyceride level (176 mg/dL; normal < 150 mg/dL). All of his cholesterol levels were within a normal range, his blood pressure was 140/75 millimeters of mercury and his CD4 cell count was 480 per cubic millimeter. We were not able to detect any viral load.


Figure 1
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  		Figure 1. Case 1. Bilateral parotid area swelling, most marked on the right side.

 
A detailed physical examination revealed that the patient had a thick neck (size 18 collar), a buffalo hump (Figure 2Go), increased abdominal girth and thinned buttocks, which required him to wear padded underwear for comfort when sitting. There was no apparent facial thinning. Several years ago, the patient underwent liposuction to reduce the buffalo hump, but it rapidly recurred.


Figure 2
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  		Figure 2. Case 1. Increased neck thickness with a dorsocervical buffalo hump.

 
Extraorally, swelling in both parotid regions was visible, most markedly on the right side. According to the patient, these swellings did not fluctuate in size when eating, and they had become a serious cosmetic issue for him. When we palpated the swellings, we found that they were painless and had a normal tissue tone and that there was no cervical lymphadenopathy. Intraorally, the mucosa was moist, and all salivary ducts demonstrated patency and a normal salivary flow.

A computed tomography (CT) scan revealed the cause of the swellings (Figure 3Go). Both parotid glands were normal in contour, size and density. However, an increased subcutaneous fat deposition, most marked on the right side, was evident at the periphery of each parotid gland. This fatty accumulation was the cause of the clinically evident facial deformity. When we explained to the patient the cause of the swellings and the possibility of their recurrence after liposuction, he decided not to seek treatment to reduce the swellings.


Figure 3
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  		Figure 3. Case 1. Computed tomography scan (axial view) showing bilateral fat depositions (arrows), which were most marked on the right side, around both parotid (p) glands.

 
Case 2. After undergoing tooth extractions, a 62-year-old man with HIV was referred to the Columbia University College of Dental Medicine’s Salivary Gland Center (SGC) because he had called his dentist’s attention to his bilateral parotid area swellings (Figure 4Go).


Figure 4
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  		Figure 4. Case 2. Bilateral parotid area swellings with bilateral loss of anterior malar area fat tissue.

 
We determined that the patient’s HIV had been diagnosed 16 years earlier. He was unaware of the exact medications that had been prescribed at that time, but eight years earlier he had begun receiving HAART that included nelfinavir, stavudine and lamivudine, which are a PI and two NRTIs, respectively. The patient also was taking atorvastin and aspirin.

Several years before we examined the patient, he had noticed a facial thinning in the malar areas associated with a simultaneous painless increase in tissue bulk in both parotid gland areas. A physical examination revealed that the patient had a buffalo hump and thin extremities. The patient had not experienced an increase in neck width or abdominal girth, nor was there any obvious decrease in the buttocks’ cushion. Laboratory studies revealed an elevation in his triglyceride level (317 mg/dL), but his cholesterol and glucose levels were normal. His blood pressure at the time of examination was 110/70 mm Hg, and his CD4 cell count was reported to be 552/mm3. We could not detect a viral load.

Intraorally, the mucosa was moist, and we observed a normal salivary flow exiting from all salivary ducts. A CT scan revealed bilateral paraparotid fat depositions (Figure 5Go). Once we explained the reason for the swellings to the patient, he decided against receiving any further treatment.


Figure 5
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  		Figure 5. Case 2. Computed tomography scan (axial view) showing bilateral fat depositions (arrows) superficially placed over both parotid (p) glands.

 

   DISCUSSION
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Salivary gland enlargement is not an unusual finding in patients with HIV and almost always is associated with the diffuse infiltrative CD8 lymphocytosis syndrome (DILS). Bilateral parotid gland swellings are seen in this subset of patients with HIV and indicate multiple lymphoepithelial cysts or a massive CD8 lymphocytic infiltration. These patients also usually have cervical lymphadenopathies and an interstitial pneumonitis. A serologic study can verify a significant CD8 cell elevation.

In the past, we often saw patients with HIV and parotid gland swellings associated with DILS in the SGC. When the HAART regimen was first used to treat HIV, we saw these patients infrequently in the SGC. In contradistinction, Patton and colleagues26 reported an apparent increase in HIV-related salivary gland disease in patients who had received HAART. Regardless, we were surprised when two patients who were long-term HAART recipients sought evaluation of their bilateral swellings of the parotid region. After taking thorough histories and conducting clinical examinations that included imaging, we were able to determine that the swellings were caused by increased depositions of subcutaneous fat in the paraparotid tissues. It is this unusual glandular area finding, which has not been reported previously, that served as the impetus for us to report these two cases.

The initial and tentative diagnosis that we made in these two cases was DILS-associated bilateral parotid gland swelling caused by lymphoepithelial cysts, a massive intraglandular lymphoproliferation or both. We considered DILS, but because HAART has altered the clinical spectrum of parotid swelling, a diagnostic dilemma existed. The CT scan solved the problem by showing normal parotid glands with increases in paraparotid subcutaneous fat. In the future, when we are evaluating patients with HIV who we suspect have LD, we will use magnetic resonance imaging, which is a more advantageous fat-imaging technique than CT scanning, to determine the diagnosis.

Differential diagnosis in patients with persistent, painless bilateral parotid gland swellings that have a normal tone must include sialosis, or sialadenosis. Diabetes, alcoholism and eating disorders are conditions that can cause sialosis. These abnormalities initiate autonomic neuropathies with sympathetic nerve dysfunction. The neurological dysregulation leads to engorgement of individual acinar cells by zymogen granules, the precursor to amylase. Sialosis can be recognized by the associated systemic disease, the clinically benign asymptomatic state and fine-needle aspiration that reveals enlarged acinar cells and the absence of pathological cytology.

Bilateral parotid gland swellings also occur in conjunction with various tumors. Lymphomas, Warthin tumors and oncocytomas develop bilaterally, but we ruled them out in the two cases when the CT scans revealed that the parotid glands were normal. Similarly, we rejected diagnoses of bilateral parotid swellings caused by Sjögren syndrome or sarcoidosis when the CT scans indicated the swellings were paraparotid. Furthermore, we eliminated these nonneoplastic entities on the basis of the physicians’ thorough medical examinations and our examinations, which included the observances of normal salivary flow.

The fatty redistribution associated with HIV LD was apparent in our patients, but not in a consistent pattern. Both patients had experienced increased parotid area fat and a dorsocervical fatty buffalo hump. The patient in case 1 had an associated increase of fat in his abdomen and neck. His fatty tissue loss was not a classic pattern; while his facial and extremity fat appeared to be normal, only his buttocks experienced a significant loss of fat. The patient in case 2 had thinned extremities and malar areas; they were the only anatomical areas that experienced fat loss.

The three metabolic complications associated with LDS (LD, dyslipidemia, insulin resistance) are not always all present. In our case reports, both patients experienced abnormal fat distribution, which frequently is seen alone, but often dyslipidemia, insulin resistance or both are present. The patient in case 1 showed signs of an abnormal glucose metabolism and had a hyper-triglyceridemia. The patient in case 2 had a significantly elevated triglyceride level, but we noted no aberrations in glucose metabolism.

The antiviral medications used by our patients in the past and at the time we examined them included NRTIs, non-NRTIs, synthetic nucleoside analogues and PIs. These medications, which are connected with LDS, caused the fat redistributions that were of concern. Attempts to improve the adipose changes in LD by altering the medication regimen have resulted in only moderate success27 and should be weighed against the possibility that the new regimen will not adequately control HIV replication.5 It has been reported, however, that substituting "within-class PIs" can improve the lipid parameters associated with dyslipidemia.28 For the patients in our case reports, decisions regarding the regimen needed to be made by their physicians, to whom we referred them for continued medical management.

Some LD fat loss may be controlled through the use of rosiglitazone. This agent causes small gains in the amounts of extremity fat, but, unfortunately, it also causes a dyslipidemia.29,30 Plastic surgery, including liposuction and a variety of soft-tissue fillers and implants, can redress cosmetic concerns and has proven to be helpful.8 Control of LD is best accomplished through diet and exercise.


   CONCLUSIONS
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Although LDS is a concern for health care practitioners who manage HIV, the changing nature of parotid gland and other related facial abnormalities may not be well-known to them. Therefore, dentists should be able to identify abnormalities of the orofacial structures that may have significant systemic implications. Although the patients in our case reports had triglyceride levels (cases 1 and 2) and glucose levels (case 1) outside the normal range, the levels did not affect the delivery of dental care. Nevertheless, the presence of HIV disease and LDS in patients with more serious metabolic and cardiovascular problems may affect dental care and require adjustments in its delivery. As dental practitioners continue to treat more medically compromised patients, knowledge of their disease processes must be expanded. Furthermore, with the advent of newer medical treatments, new manifestations will be encountered, and they will demand attention.


   FOOTNOTES
 

Dr. Mandel is the director, Salivary Gland Center, Columbia University College of Dental Medicine, New York City, and an assistant dean and clinical professor, Division of Oral and Maxillofacial Surgery, Columbia University College of Dental Medicine, New York-Presbyterian Hospital, New York City. Address reprint requests to Dr. Mandel at Division of Oral and Maxillofacial Surgery, Columbia University College of Dental Medicine, New York-Presbyterian Hospital, 630 West 168th St., New York, N.Y. 10032.


Dr. Alfi is a resident, Oral and Maxillofacial Surgery, Columbia University College of Dental Medicine, New York-Presbyterian Hospital, New York City.


   REFERENCES
TOP
 ABSTRACT
 CASE REPORTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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