LIPODYSTROPHY SYNDROMES

Emily BrennanPGY5 EndocrinologyWednesday September 2, 2015

OBJECTIVES

The objectives of this talk are to review: Lipodystrophy Syndromes Classification/Clinical Features of Lipodystrophy Syndromes Focus on HIV Related Lipodystrophy Management of Metabolic Complications Novel Treatment Options

CASE

59 year old white male

Referred by his HIV specialists for body composition changes, diabetes and dyslipidemia.

He was diagnosed with HIV 10 years earlier, and immediately started on HAART with excellent immunological and virological response.

Within 12 months of HAART, he began to notice reduced fat in his buttock and thighs, prominent in the veins on his legs and changes to his facial appearance. He also noticed increased fat in his abdomen.

CASE

CASE

He developed high triglycerides and diabetes, and he was started on gemfibrozil and insulin. He also stopped HAART.

His DM and hyperlipidemia did not resolve after HAART discontinuation. One year later, his CD4 count decreased to under 200. Therefore, his antiretrovirals were restarted.

What are your next steps in management?

QUESTION

What is the most common form of lipodystrophy world-wide?

1. Dunnigan’s Lipodystrophy

2. Congenital Generalized Lipodystrophy

3. HIV-Associated Lipodystrophy

4. CANDLE Syndrome

QUESTION

What are the major metabolic complications of lipodystrophy?

1. insulin resistance/diabetes

2. hypertriglyceridemia

3. fatty liver

4. all of the above

WHAT IS LIPODYSTROPHY?

Definition: Heterogeneous group of rare acquired and inherited disorders

characterized by selective loss of adipose tissue (lipoatrophy)

In some cases, there is accumulation of fat (lipohypertrophy) in other regions of the body

Generalized vs Localized vs Partial

WHAT ARE THE COMPLICATIONS? Cosmetic

Insulin resistance

Severe hyperlipidemia

Fatty Liver

PCOS

Increased metabolic rate

Nephrotic syndrome

WHAT ARE THE COMPLICATIONS?

• The extent of lipoatrophy correlates with the severity of metabolic abnormalities.

• The strong bond between fat loss and metabolic abnormalities demonstrates the significance of adipose tissue as dynamic endocrine organ.

ADIPOSE TISSUE

Highly active metabolic endocrine organ

Mainly composed of adipocytes, but also is an intricate network of connective tissue, nerve cells, stromovascular cells and immune cells

Adipose tissue is extremely responsive to hormonal signals and to the demands of the CNS Secretes sex steroids and glucocorticoids

Insulin and steroids induce transcription factors to prompt the pre-adipocyte to being differentiation into a standard adipocyte Once there is excess substrate (“food”) available, lipids droplets form within the adipocyte and

subsequently differentiate the adipocytes level of maturity

ADIPOSE TISSUE

Lipid droplets are small organelles that store triglycerides intracellularly They form as vesicles within the endoplasmic

reticulum that fuse and accumulate

As these droplet grow in size and bulk, the adipocyte increases in bulk, and this process is essentially reversed in periods of fasting/starvation

Normal adipose tissue protects again lipo- and glucotoxicity (via adipocyte differentiation)

MECHANISM OF DISEASE

Adipocytes provide a place to store lipids; when these cells are absent, lipid will accumulate in the muscle, liver and other areas of the body

This accumulation of triglycerides is thought to cause metabolic instability, including insulin resistance, hepatosteatosis, and often cirrhosis

LIPODYSTROPHY CLASSIFICATION Congenital

Generalized Congenital generalized lipodystrophy (CGL) Mandibuloacral dysplasia Autoinflammatory syndromes (CANDLE, JMP)

MDP syndrome Neonatal progeroid syndrome

Regional Autosominal dominant familial partial lipodystrophy (FPL) = Kobberling, Dunnigan

SHORT syndrome

Acquired

Generalized AGL

Regional HIV-related lipodystrophy APL (autoimmune, MPGN-associated)

Localized Localized lipodystrophy (drug, panniculitis, pressure, idiopathic)

CONGENITAL GENERALIZED LIPODYSTROPHY

CONGENITAL GENERALIZED LIPODYSTROPHYMetabolic Abnormalities Insulin resistance is typically seen in an early age

DM usually develops in teens, ketosis is rare DM usually refractory to insulin

Hypertriglyceridemia Pancreatitis

Serum leptin are low Consistent with near total absence of body fat

Depiction A Congenital Generalized Type 1 Generalized lack of fat Extreme muscularity Acanthosis nigricans in the groin

Acromegaloid features

Depiction B Congenital Generalized Type 2 (seipin)

Generalized lack of fat Extreme muscularity Acanthosis nigricans in the groin

Acromegaloid features HCOM + mild mental retardation

CONGENITAL PARTIAL LIPODYSTROPHIES

Depiction C Familial partial lipodystrophy Dunnigan variety (missense mutation in lamins A+C)

Loss of fat in arms, legs trunk, excess fat in face/neck

Depiction D Familial partial lipodystrophy Heterozygous missense mutation in PPAR-gamma

Loss of fat in arms, legs; face and neck excess fat

More prominent loss in forearms and calves than in upper arms/thighs

ACQUIRED LIPODYSTROPHIES

Depiction C Acquired Generalized Lipodystrophy

8 yr old German boy experienced generalized loss of SC at age 3

marked acnthosis nigricans in the neck axilla, and groin.

Developed Crohn’s at age 8.

Depiction D Acquired Partial Lipodystrophy Marked loss of SC fat from face, neck, arms, chest, abdomen

Increased SC fat deposition in lower extremities

Depiction E 39 yo male with HIV on HAART Marked loss of SC fat from the face and limbs

Increased in neck, showing dorsal fat pad.

Abdomen protuberant due to excess intraabdominal fat

HIV LIPODYSTROPHY SYNDROME A new phenomenon was seen with the introduction of HAART Changes in body composition, including subcutaneous fat wasting and central fat accumulation

Often developed in conjunction with dyslipidemia and insulin resistance Now, it is the most common form of lipodystrophy

Originally, thought it was due to protease inhibitors

More recently, thought to be multifactorial with contributions from the HIV medications, patient related factors, and the HIV infection itself

CLINICAL FEATURES OF HIV LIPODYSTROPHY Generalized depletion of subcutaneous fat Commonly observed in the face, buttocks, legs and arms Some areas spared with excess fat accumulation

Occurs in 13-34% on HAART; typically over 2 or more years Worsens with ongoing therapy Does not reverse with d/c of therapy

PATHOPHYSIOLOGY

PIs Inhibit ZMPSTE24, resulting in accumulation of toxic farnesylated prelamin A Alter transcription factors in lipogenesis and adipose differentiation They may inhibit GLUT4 expression causing insulin resistance

NRTIs (especially zidovudine and stavudine) May inhibit mitochondrial polymerase-gamma and cause mitochondrial toxicity

ASSOCIATED METABOLIC ABNORMALITIES Dyslipidemia See increased LDL and TGs; decreased HDL

Certain PIs may increase TG synthesis, but variability between individual agents

In addition, the increase in visceral fat and reduction in lower body subcutaneous fat independently are associated with dyslipidemia

ASSOCIATED METABOLIC ABNORMALITIES Diabetes / Insulin Resistance

Risk is increased in HAART-treated HIV infected patients compared to HIV-uninfected controls

Thought to be multifactorial in etiology with contributions from: HIV itself Patient related factors (genetics, weight, lifestyle) Antiretroviral therapy

TREATMENT CONSIDERATIONS Stopping or Switching HAART

Lipoatrophy

Lipohypertrophy

Dyslipidemia

Insulin Resistance/ Diabetes

TREATMENT CONSIDERATIONS Stopping or Switching HAART AIDS 2000 Design: Prospective study of 26 Causasian men with HIV-1 viral loads under 500 copies/ml while on HAART

Intervention: interruption of HAART for 7 weeks (median)

Measure: lipids, glucose, insulin levels, 24-hr urinary free cortisol

Conclusion: relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and TG levels. No change observed in insulin.

TREATMENT CONSIDERATIONS Stopping or Switching HAART Design: 5,472 Patients, RCT Intervention: patients with HIV infection who had a CD4 count over 350 were randomly assigned to either continuous use of HAART vs episodic use (deferred use until CD4 count under 250, and until the therapy increased the count to more than 350

Primary End Point: development of opportunity disease/death from any comes Secondary: major cardiovascular, renal, hepatic diseases

TREATMENT CONSIDERATIONS Switching HAART Switching has been extensively evaluated in their effect on reversing body composition and metabolic abnormalities

Abacavir or tenofovir are “less toxic” than stavudine or zidovudine May require collaboration between HIV specialists, endocrinologists, and pharmacists

TREATMENT CONSIDERATIONS Lipoatrophy TZDs (rosi) has shown efficacy for increasing subcutaneous fat in non-HIV lipoatrophy

Mixed results for HIV-infected patients RCT with pioglitazone (48 weeks) showed significant improvement in limb circumference, skin fold

thickness; but change in fat was not perceptible to patients

Statins Small RCT, pravastatin treated patients for 16 weeks showed increase in limb fat compared to

placebo

UridineMay prevent/reverse mitochondrial toxicity in patients treated with stravudine

Surgery Facial fillers, reconstruction by plastic surgeons = improvement in QoL, decrease anxiety/depression Autologous fat transplantation

TREATMENT CONSIDERATIONS Lipohypertrophy = very difficult to treat Lifestyle

Only modest improvements have been seen with resistance training, aerobic exercise

Metformin Decreases visceral fat in HIV-infected patients; variable results Metformin + exercise appears to have use treating lipohypertrophy

GH Axis HIV infected patients with body composition changes also show reduced GH mean pulse amplitude,

and may be correlated to central fat accumulation

Surgery Liposuction can be successful (particularily for dorsocervical fat pad accumulation) Recurrence is a problem

Phase III trial

46 men with HIV on HAART

Design: RCT, double blind, single centre

Intervention: 0.7 mg/day rhGH vs placebo; given daily between 1-3 pm for 40 weeks

Conclusion: daily 0.7 mg rhGH x 40 weeks reduced abdominal visceral fat and trunk fat mass in HIV-infected patients

TREATMENT CONSIDERATIONS Dyslipidemia Recommended to use the CCS Lipid Guidelines Preferred agent: statins Need to consider risk of pharmacologic interactions

Pravastatin and fluvastatin are safe with ritonavir Simavastatin and lovastatin are contraindicated

TREATMENT CONSIDERATIONS Diabetes / Insulin Resistance Continue to use the CDA guidelines Insulin sensitizers may be have a role

Reports shown that HbA1c may be inappropriately low in patients with HIV, thereby, underestimated glycemia ? Due to chronic low-level hemolytic state from viral infection or HAART

Question: what is the best way to monitor DM in patients with HIV?

Population: 59 patients with HIV and DM

Method: compared HbA1c with finger-stick glucose averaged over 3 months vs fructosamine levels with finger-stick glucose averaged over 6 weeks

Conclusion: fructosamine was NOT more accurate than HbA1c

NOVEL TREATMENT OPTIONS

Leptin is an adipocyte hormone first discovered in 1994

Murine studies demonstrated that leptin decreased weight, food intake, and body fat percentage in obsess mice

It has a central role in energy homeostasis and its level are directly proportional to adipose mass (no fat = no leptin)

The circulating level of leptins reflects the availability to energy store in adipose tissue and acute changes in energy intake

LEPTIN

Central Actions: Works at hypothalamus promote satiety / decrease food intake

Leptin may be fully / partially responsible for starvation-induced changes in the neuro-endocrine axes, including low reproductive, thyroid, and IGF hormones

Peripheral Actions: Decreases gluconeogenesis in the liver (overlaps with insulin pathways)

Prevents lipid accumulation in skeletal muscle (“lipotoxicity”)

May preserve lean tissues during weight loss

METRELEPTIN

Metreleptin (Myalept) is a recombinant analogue of human leptin First approved in 2013 in Japan FDA approved it in Feb 2014 for treatment of congenital generalized lipodystrophy, non-HIV associated acquired generalized lipodystrophy

NEJM LEPTIN-REPLACEMENT

Design: 9 female patients with lipodystrophy and serum leptin levels under 4 ng per mL received recombinant human leptin twice daily for 4 months at escalating doses to achieve low, intermediate, and high physiological replacement levels

Outcomes: look for improvement in insulin resistance diabetes, hypertriglyceridemia

LONGER TERM LEPTIN DATA

Studied 9 patients (5 females and 4 males) with genetic lipodystrophies 6 were children under 9 Studied metreleptin self-administered therapy SC; dose according to body weight Duration of treatment 9 months to 5 years

Randomized, blinded, crossover study in 7 men

Results: Improved fasting insulin, reduced insulin resistance Body weight, and fat mass decreased (14.6%) No change in LDL or TG No change in HIV control

6 month study; open-label, proof of principle8 men with HIV-infection with lipoatrophyFollowed for 6 monthsResults:• Visceral fat decreased by 32%, no increase in peripheral fat• LDL decrease by 20%; HDL increased• TG and fasting insulin decreased

BACK TO THE CASE…

Issues to address: Diabetes control = follow guidelines; caution with following A1c Lipid control Lipoatrophy/Lipohypertrophy = consider metformin/exercise/TZD/cosmetics Quality of Life/Mood

As our management of HIV improves, we need to consider all these long term treatment considerations.

QUESTION

What is the most common form of lipodystrophy world-wide?

1. Dunnigan’s Lipodystrophy

2. Congenital Generalized Lipodystrophy

3. HIV-Associated Lipodystrophy

4. CANDLE Syndrome

QUESTION

What are the major metabolic complications of lipodystrophy?

1. insulin resistance/diabetes

2. hypertriglyceridemia

3. fatty liver

4. all of the above

COMMENTS/QUESTIONS?

REFERENCES

Greenspan’s

Mayo Clinic

Garg A. Lipodystrophies: Genetic and Acquired Body Fat Disorders. JCEM. 2011

Garg A. Acquired and Inherited Lipodystrophies. NEJM 2004.

The Clinical Approach to Endocrine and Metabolic Diseases. Volume 1.