Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug antiretroviral regimens that include human immunodeficiency virus-1 (HIV-1) protease inhibitors are associated with distinct lipodystrophy, hypertriglyceridemia, hyperinsulinemia, and deposition of visceral abdominal adipose tissue. To determine whether these findings are related to abnormalities of adrenal function, we compared the hypothalamic-pituitary-adrenal axes of HIV-positive patients who had evidence of protease inhibitor-associated lipodystrophy (PIAL), control volunteers (CON), and patients with Cushing's syndrome (CS). To elucidate the metabolic consequences of the observed lipodystrophy, we measured basal serum lipids and compared glucose and insulin concentrations during an oral glucose tolerance test. Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean +/- SD, 76 +/- 51 nmol/day) was significant lower than those in CON (165 +/- 64 nmol/day; P < 0.001) and CS (1715 +/- 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 +/- 23 micromol/day) than in CON (17 +/- 8 micromol/day; P < 0.001), although lower than that in CS (74 +/- 47 micromol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 +/- 5.63 mmol/L) than in CS (1.78 +/- 0.83 mmol/L; P < 0.001) or CON (1.36 +/- 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min. We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.
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PMID:Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. 1037 88

A novel lipodystrophy syndrome (characterized by insulin resistance, hypertriglyceridemia, and fat redistribution) has recently been described in human immunodeficiency virus (HIV)-infected patients. However, investigation of the lipodystrophy syndrome has generally been limited to men; and a comprehensive evaluation of insulin, lipids, and regional body composition has not been performed in the expanding population of HIV-infected women. In this study, we assessed fasting insulin, lipid levels, virologic parameters, and regional body composition, using dual-energy x-ray absorptiometry, in a cohort of 75 HIV-infected women (age, 25-46 yr), in comparison with 30 healthy weight-matched premenopausal control subjects. HIV-infected women demonstrated significant truncal adiposity (38.5 +/- 0.9 vs. 34.9 +/- 1.3%, P < 0.05) hyperinsulinemia (15.9 +/- 1.5 vs. 7.5 +/- 0.6 microU/mL, P < 0.001) and an increased insulin-to-glucose ratio (0.2 +/- 0.02 vs. 0.1 +/- 0.03, P < 0.001), compared with control subjects. Insulin and the insulin-to-glucose ratio were increased, even among HIV-infected patients with low body weight (<90% of ideal body weight) (insulin, 13.3 +/- 2.8 microU/mL, P < 0.01 vs. control; insulin/glucose, 0.2 +/- 0.04, P < 0.01 vs. control). Insulin and the insulin-to-glucose ratio were most significantly elevated among patients with increased truncal adiposity (insulin, 28.2 +/- 3.2 microU/mL, P < 0.001 vs. control; insulin/ glucose, 0.32 +/- 0.04, P < 0.001 vs. control). In contrast, no differences in insulin were seen in relation to protease inhibitor (PI) use. Similarly, HIV-infected women also demonstrated significant hypertriglyceridemia (144 +/- 15 vs. 66 +/- 23 mg/dL, P < 0.01 vs. controls), which was present even among low-weight patients (148 +/- 32 mg/dL, P < 0.001 vs. control) but was not related to truncal adiposity or PI usage. These data demonstrate significant hyperinsulinemia and truncal adiposity in HIV-infected women. Our data suggest that these metabolic abnormalities occur at baseline in HIV-infected women, independent of PI use. However, these data do not rule out a direct effect of PI therapy on fat metabolism or indirect effects of PI therapy to further worsen glucose and lipid homeostasis in association with weight gain and disease recovery.
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PMID:Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. 1037 89

Recent research has shown abnormal lipids in acquired immunodeficiency syndrome (AIDS). In human immunodeficiency virus (HIV) infection hypocholesterolaemia, hypertriglyceridaemia and also low high density lipoprotein (HDL)-cholesterol have all been described. In addition, increased dense low density lipoprotein (LDL) particles and also lipoprotein (a) have been observed in some patients. The use of the protease inhibitors has been associated with diabetes mellitus and also features of insulin resistance. This article looks at these lipid abnormalities in detail and discusses possible therapeutic options that may be available, in order to address them.
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PMID:Abnormal lipids and the acquired immunodeficiency syndrome: is there a problem and what should we do about it? 1041 76

Type I interferons (IFN-alpha/beta), products of the innate immune system, can modulate immune function whereas proinflammatory IFN-gamma (type II IFN), a product of the acquired immune system upregulates inflammation and enhances cell mediated immunity. We have proposed a unifying hypothesis of the origin of autoimmunity as a type I IFN immunodeficiency syndrome involving inadequate regulation of the acquired immune system product IFN-gamma by the IFN-alpha/beta innate immune system. The common theme of ingested type I IFNs in autoimmunity is inhibition of proinflammatory type II IFN systemically or at the target organ. In multiple sclerosis (MS) and insulin-dependent diabetes mellitus (IDDM) at the target organ, and in rheumatoid arthritis (RA) as a regulator of other proinflammatory cytokines, IFN-gamma is the nexus of inflammation in autoimmunity. Ingested type I IFNs counteract type II IFN, overcome the relative lack of type I IFN activity, and ameliorate autoimmunity. The administration of type I IFNs (IFN-alpha/beta) via the gut offers an exciting alternative to systemic application for overcoming the type I IFN immunodeficiency in autoimmunity. Successful use of ingested type I IFN in three separate prototypical autoimmune diseases suggests a broad antiinflammatory therapeutic profile for this technology.
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PMID:Autoimmunity is a type I interferon-deficiency syndrome corrected by ingested type I IFN via the GALT system. 1047 27

Fat redistribution in the setting of protease inhibitor use is increasingly common and is associated with insulin resistance in human immunodeficiency virus (HIV)-infected patients. However, little is known regarding the factors that may contribute to abnormal insulin regulation in this population. We assessed fasting insulin levels in HIV-infected men and determined the relationship among insulin, body composition, endogenous gonadal steroid concentrations, and antiviral therapy in this population. We also determined the effects of exogenous testosterone administration using the homeostatic model for insulin resistance (HOMA IR) in hypogonadal HIV-infected men with the acquired immunodeficiency syndrome wasting syndrome. Fifty HIV-infected men with acquired immunodeficiency syndrome wasting were compared with 20 age- and body mass index (BMI)-matched healthy control subjects. Insulin concentrations were significantly increased in HIV-infected patients compared to those in control patients (16.6+/-1.8 vs. 10.4+/-0.8 microU/mL; P<0.05) and were increased in nucleoside reverse transcriptase (NRTI)-treated patients who did not receive a protease inhibitor (PI; 21.7+/-4.3 vs. 10.4+/-0.8 microU/mL; P<0.05). Insulin concentrations and HOMA IR were inversely correlated with the serum free testosterone concentration (r = -0.36; P = 0.01 for insulin level; r = -0.30; P = 0.03 for HOMA), but not to body composition parameters, age, or BMI. In a multivariate regression analysis, free testosterone (P = 0.05), BMI (P<0.01), and lean body mass (P = 0.04) were significant. Lower lean body mass and higher BMI predicted increased insulin resistance. The HIV-infected patients demonstrated an increased trunk fat to total fat ratio (0.49+/-0.02 vs. 0.45+/-0.02; P<0.05) and an increased trunk fat to extremity fat ratio (1.27+/-0.09 vs. 0.95+/-0.06, P = 0.01), but a reduced extremity fat to total fat ratio (0.44+/-0.01 vs. 0.49 + 0.01; P = 0.02) and reduced overall total body fat (13.8+/-0.7 vs. 17.2+/-0.9 kg; P<0.01) compared to the control subjects. Increased truncal fat and reduced extremity fat were seen among NRTI-treated patients, but this pattern was most severe among patients receiving combined NRTI and PI therapy [trunk fat to extremity ratio, 1.47+/-0.15 vs. 0.95+/-0.06 (P<0.01); extremity fat to total fat ratio, 0.40+/-0.02 vs. 0.49+/-0.01 (P<0.05)]. Insulin responses to testosterone administration were investigated among 52 HIV-infected men with hypogonadism and wasting (weight <90% ideal body weight and/or weight loss >10%) randomized to either testosterone (300 mg, im, every 3 weeks) or placebo for 6 months. Testosterone administration reduced HOMA IR in the HIV-infected men (-0.6+/-0.7 vs. +1.41+/-0.8, testosterone vs. placebo, P = 0.05) in association with increased lean body mass (P = 0.02). These data demonstrate significant hyperinsulinemia in HIV-infected patients, which can occur in the absence of PI use. In NRTI-treated patients not receiving PI, a precursor phenotype is apparent, with increased truncal fat, reduced extremity fat, and increased insulin concentrations. This phenotype is exaggerated in patients receiving PI therapy, with further increased truncal fat and reduced extremity fat, although hyperinsulinemia per se is not worse. Endogenous gonadal steroid levels are inversely related to hyperinsulinemia in HIV-infected men, but reduced lean body mass and increased weight are the primary independent predictors of hyperinsulinemia. Indexes of insulin sensitivity improve in response to physiological androgen administration among hypogonadal HIV-infected patients, and this change is again related primarily to increased lean body mass in response to testosterone administration.
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PMID:Fasting hyperinsulinemia in human immunodeficiency virus-infected men: relationship to body composition, gonadal function, and protease inhibitor use. 1063 60

Lipodystrophies, characterized by reduction of subcutaneous fat over part or all of the body surface, are uncommon. Their causes are unknown. Recently, lipodystrophy has been reported in human immunodeficiency virus (HIV)-infected patients taking protease inhibitors, which have been recommended since 1996 as standard therapy for HIV disease in combination with nucleoside analogues. In these cases, lipodystrophy consists of an association of peripheral lipoatrophy with central adiposity. We report four HIV-infected men on protease inhibitors who developed a disfiguring lipodystrophy. In three of them, the protease inhibitor was administered for a mean duration of 21.5 months (range 19-23) with good immunological and virological responses. Patient 4 had been treated for 2 years with successive combinations of protease inhibitors with nucleoside analogues without success. The four patients progressively developed an increase in abdominal girth associated with fat wasting of the face and legs. Two of them had recurrent paronychia of the great toes. Triglyceride levels were moderately increased in all patients, and one had a slightly increased cholesterol level. One patient had elevated glucose and insulin plasma levels during a glucose tolerance test. In two patients, a deep biopsy taken from the thigh showed thinning of the subcutaneous fat without other morphological changes. Computed tomographic scans of the face and abdomen confirmed the loss of almost all subcutaneous fat of the cheek and temporal regions, and abdominal perivisceral fat accumulation. For patients 1-3, the protease inhibitor was replaced by a non-nucleoside reverse transcriptase inhibitor. Nine months later, dysmorphic changes had not regressed, but lipid abnormalities had returned to normal and the paronychia had disappeared.
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PMID:Lipodystrophy associated with protease inhibitors. 1073 57

The nutritional condition of children with human immunodeficiency virus (HIV) infection continues to be a problem both in developed and developing countries. HIV-infected children grow below normal standards in both height and weight when compared with HIV-exposed non-infected children. These patterns persist over time. It is possible that acute infectious episodes and increased HIV viral burden contribute to decrements in all growth variables. Potential aetiologies for abnormal growth include inadequate dietary intake, gastrointestinal malabsorption, increased energy utilization and psycho-social problems. It is likely that all these factors contribute to the growth problems of these children to some extent. With the development of protease inhibitor anti-retroviral therapy and highly-active anti-retroviral treatment regimens, children with HIV infection in developed countries are living longer with a chronic illness. New nutritional problems have arisen with the development of the fat redistribution syndrome or lipodystrophy. Emerging problems are now being recognized, with the development of insulin resistance and truncal obesity which may potentially lead to premature cardiovascular disease.
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PMID:Nutrition in paediatric human immunodeficiency virus infection. 1082 85

Human immunodeficiency virus (HIV) protease inhibitor (PI) therapy is frequently associated with a syndrome increasingly referred to as lipodystrophy syndrome, which is characterized by peripheral lipoatrophy, fat accumulation within the abdomen, in the breasts of women, and over the cervical vertebrae ("buffalo hump"), hyperlipidemia, and insulin resistance. In the largest study to date, peripheral lipoatrophy (an estimated 0.35-kg fat loss per month overall from the face, limbs, and upper trunk) was observed in association with all licensed PIs after a median 10 months of PI therapy. Diabetes mellitus type II appears to be a related, but less common, adverse effect. The lipodystrophy syndrome may be a result of the inhibition of 2 proteins involved in lipid metabolism that have significant homology to the catalytic site of HIV protease-namely, cytoplasmic retinoic acid binding protein type 1 and low density lipoprotein-receptor-related protein.
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PMID:HIV protease inhibitor-related lipodystrophy syndrome. 1086 Aug 98

Treatment of human immunodeficiency virus type 1 (HIV-1) infection with regimens that include protease inhibitors (PIs) has contributed to marked improvements in HIV-related disease progression and mortality. Five PIs are approved by the US Food and Drug Administration and have potent activity in vitro. PIs with 2 nucleoside analogue reverse transcriptase inhibitors have demonstrated prolonged suppression of HIV-1 replication in treated patients and improvements in disease progression and mortality. PIs combined with nonnucleoside reverse transcriptase inhibitors or other PIs produce marked antiretroviral effects. Although not all patients have prolonged responses to PIs, and salvage treatment has had mixed results for patients who have not responded to initial PI therapy or whose HIV RNA levels have relapsed during such therapy, newer PIs currently being developed hold promise. Most patients can successfully tolerate PI-including regimens; however, long-term side effects, such as body fat redistribution, insulin resistance, and increased serum lipids, are now being observed in some patients receiving PI-including therapy.
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PMID:HIV-1 protease inhibitors. 1086 Sep 1

Human immunodeficiency virus (HIV) protease inhibitors (PI) may alter lipid metabolism in patients with acquired immunodeficiency syndrome (AIDS). However, the influence of dietary fat on the metabolic effects of PI therapy remains unknown. AKR/J mice were fed high or low fat diets and treated with the PI indinavir (IDV), nelfinavir (NFV), saquinavir (SQV) or amprenavir (APV) by subcutaneous delivery for 2 wk. Serum concentrations of glucose, insulin, triglyceride, free fatty acid, glycerol, pancreatic lipase, bilirubin, alkaline phosphatase, blood urea nitrogen and PI, and interscapular and epididymal fat weights were determined. Some metabolic effects of PI were dependent on diet. IDV- and NFV-treated mice had greater serum glucose concentration and body weight; IDV-treated mice had lower serum insulin; NFV-treated mice had greater interscapular fat mass; and SQV treated mice had lower serum triglyceride concentration than control mice fed the low but not the high fat diet. In contrast, NFV- and IDV-treated mice had greater triglyceride concentration and blood urea nitrogen, and SQV treated mice had greater serum cholesterol than control mice fed the high but not the low fat diet. The serum concentration of SQV was lower in mice fed the high fat compared with the low fat diet. Other effects were not dependent on diet. IDV- and NFV-treated mice had greater fatty acids, and IDV-treated mice had greater pancreatic lipase, bilirubin and alkaline phosphatase than control mice fed either diet. APV treatment had little effect on these serum measurements. Thus, changes in dietary fat can influence some but not all of the effects of PI on metabolism. Furthermore, each PI produces different effects in vivo, indicating that various PI affect distinct metabolic pathways.
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PMID:Dietary fat alters HIV protease inhibitor-induced metabolic changes in mice. 1095 36


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