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«Una nuova malattia rara endocrinologica: la lipodistrofia»
Dottoressa Donatella Gilio
Giovanni CeccariniCentro Obesità e Lipodistrofie
U.O. Endocrinologia I Azienda Ospedaliero-Universitaria Pisana
Definition
Lipodystrophies are heterogeneousdisorders (> 40 forms) characterized by:
any condition resulting in fat tissueloss (and redistribution), causing
defective metabolism of fat, reducedprotective factors (leptin etc) and ectopic
lipid storage
Fat apoptosis: a model of inducible lipoatrophy
Pajvani, Nature Medicine 2005
Liver, control
Liver, FAT-ATTAC
Mechanism of disease
TG synthesis
VLDL production
Liver Steatosis
Hepatic glucose production
b-cell disfunctionGlucose uptake
Insulin resistance, hypertriglyceridemia, Liver disease
Pancreas
Bindlish S, Postgrad. Med, Diabetes Review, 2011
Hypothyroidism Thyroxine
GH deficit Recombinant human GH
Adrenal (cortisol) Hydrocortisone
Adrenal (aldosetrone) Fludrocortisone
Hypogonadism Te/E2/progestins
Vitamin D deficiency Colecalciferol
Hypoparathyroidism 1-86 human PTH
Type I Diabetes Insulin
Adipokine defect Recombinant Leptin
Lipodystrophy is an endocrine disease
Lipodystrophy: classification
Congenital or familiar Acquired
Generalized Partial Generalized Partial
Leptin and adiponectin levels in lipodystrophy
Haque J Clin Endocrinol Metab 2002
Congenital or Familiar lipodystrophies
AGPAT2, BSCL2, PTRF, CAV1,PIK3R1, POLD1,KCNJ6, BANF1,ZMPSTE24,
SPRTN, ERCC6,ERCC8, LMNA
LMNA, PPARg, PLIN1,CIDEC, LIPE, AKT2, CAV1,
FBN1,WRN/RECQL2, PCYT1A, RECQL3, POLR3A, PSMB8
Generalized Partial
Involvedgenes
Type
Diagnosis and treatment of lipodystrophy: a step by step approach. Araujo-Vilar D and Santini F. JEI 2018
Vatier et al. 2013
Congenital Generalized Lipodystrophy (CGL-1)
• Autosomic recessive
• Prevalence 1:1.000.000
• Muscolar appearance
• Prominent veins
• Acromegaloid features
• Prominence of umbilicus or umbilical hernias
• Hepatomegaly and/or splenomegaly
• Acanthosis nigricans
• Mild hirsutism and clitoridomegaly in female patients
• Bone cysts
Agarwal and Garg 2003 and 2006
Congenital Generalized Lipodystrophy (CGL-1)
Familiar Partial Lipodystrophy type 2 (Dunnigan Syndrome)
• Autosomic dominant
• Prevalence unknown
• Loss of fat affecting limbs, buttocks, and hips
• Loss of fat occurring around puberty
• Face and neck excess fat accumulation
• Cushingoid appearance
• Muscolar appearance
• Hepatomegaly and/or splenomegaly
• Mild hirsutism and hypertrophy of labia majora
• Irregular mestrual periods with polycystic ovaries
• Myocardial hypertrophy, and/or cardiac conduction system disorders
LMNA-linked lipodystrophies
Bidault et al 2011 Saha et al 2010
Familiar Partial Lipodystrophy type 1 (Köbberling Syndrome)
• Dominant or polygenic pathogenesis
• Prevalence unknown
• Obese and significant accumulation of abdominal fat• Lipoatrophy most evident in the hips and lower extremities
• Loss of fat occurring early in life
• Face and neck excess fat accumulation
• Hepatomegaly and/or splenomegaly
• Severe hypertriglyceridemia
• Specific cutoffs for thickness and distribution of SAT that can be useful
Kobberling Syndrome (FPLD-1)
Trunk fat / Lower limbs fat
Cut-Off Sensitivity Specificity
Subscapular/calf skinfolds 3.477 89 % 84 %
Trunk fat mass / Lower limbs fat mass (Kg)
2.153 89 % 78 %
Trunk fat mass / Lower limbs fat mass (%)
1.282 81 % 87 %
Endocrine, 2016
Men Women
Garg, JCEM 2000
Gender differences in subcutaneous fat distribution
IMPORTANCE OF SC LEG FAT MASS
Stefan, Cell Metab 2017
Udler and Florez 2018
Insulin Processing/Secretion
Lipodystrophy-like IR
ObesityIR
InsulinSynthesis
Liver IR
Beta Cell Insulin Resistance (IR)
TYPE 2 DIABETES GENETIC LOCI: PHENOTYPIC CLUSTERS
Acquired lipodystrophy
Acquired generalizedlipodystrophy
(Lawrence Syndrome)
- Acquired partial lipodystrophy(Barraquer-Simons)
- Acquired partial lipodystrophyafter bone marrow transplant
- Paraneoplastic lipodystrophy
- HIV-associated lipodystrophy
Generalized Partial
Forms
Type
Diagnosis and treatment of lipodystrophy: a step by step approach. Araujo-Vilar D and Santini F. JEI 2018
Acquired generalized lipodystrophy (Lawrence Syndrome)
• More frequent in F > M (3 :1)
• Pathogenesis likely autoimmune
• Onset childhood or adolescence
• Onset with pannculitis in 1/3 patients
• Generalized fat loss (30-50% palms and soles)
• Preserved retro-orbital and bone marrow fat
• Progression: weeks, months, years
• Mean age at onset of Type 2 DM 16 yrs
• Very low leptin levels, increased appetite
• Increased risk of limphoma (prevalence 7 %)
Misra et al, 2003, Garg 2004, Garg 2011, Brown et al 2016, Gupta el al 2017
Dr Robert Daniel Lawrence 1892 – 1968
Acquired lipodystrophy
Acquired partial lipodystrophy (Barraquer-Simons)
• More frequent in F > M 4 : 1
• Cephalocaudal pattern of sc fat loss
• Onset childhood or adolescence (mean age 7-8 yrs)
• Infectious illnesses have been reported to precede the onset of APL
• Lower prevalence of Type 2 DM (35 %) compared to AGL
• 50-70 % show C3 and presence of IgG «Nefritic Factor», 30 % MP glomerulonephritis
• Associated autoimmune diseases 10-30%
Misra et al, 2004, Garg 2004, Garg 2011, Brown et al 2016, Gupta el al 2017
Core clinical characteristic for lipodystrophy•Loss or absence of subcutaneous body fat in a partial or generalized fashion
•Loss of subcutaneous body fat, occurring around puberty, in the extremities and/or gluteal region with sparing of fatloss or accumulation of excess fat in the face and neck or intra-abdominal area
Supportive clinical characteristics for lipodystrophy:• Presence of diabetes with evidence of svere insulin resistance (high doses of insulin, eg, ≥200 U/day/Kg/day)
o Acanthosis nigricans, PCOS or PCOS-like symptoms (Hyperandrogenism, oligomenorrhea)
• Presence of hypertriglyceridemiao Severe hypertriglyceridemia (≥500 mg/dL)o Triglyceride levels that are non-responsive to therapy and/or modifications to diet (≥250 mg/dL)o Hystory of pancreatitis associated with hypertriglyceridemia
• Evidence of hepatic steatosis or steatohepatitiso Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease
• Family hystory of similar physical appearance and/or history of fat loss• Prominent muscularity and phlebomegaly (enlarged veins) in the extremities• Disproportionate hyperphagia (cannot stop eating, waking up to eat, fighting for food)
Clinical characteristics that increase the suspicion of LipodystrophyModified from AACE consensus statement on LD, Handelsman Endocrine Practice, 2013
Diagnosis and treatment of lipodystrophy: a step by step approach. Araujo-Vilar D and Santini F. JEI 2018
Lipodystrophy: diagnosis
Treatment of Lipodystrophy Syndromes
Recombinant human leptin
Psychological support and plastic surgery
Conventional therapies to preventor ameliorate the comorbidities
Diet and physicalactivity
In February 2014 Metreleptin wasapproved by FDA as replacement therapyto treat the complications of leptindeficiency in patients with generalizedlipodystrophy
In July 2018 Metreleptin was approved by EMA asreplacement therapy to treat:
CGL and AGL (> 2 yrs) FPLD2, APL (>12 yrs), with poor metabolic
control under standard treatments
Diagnosis and treatment of lipodystrophy: a step by step approach. Araujo-Vilar D and Santini F. JEI 2018 apr 27