«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