MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Rizikové faktory, zhoršující vlivy a možné příčiny

4-tertiary-Octylphenol (4-t-OP)

  • Chemical is found in many personal care products and plastic products
  • Has weak estrogenic activity.
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Acquired partial lipodystrophy (APL; BARRAQUER-SIMONS syndrome)

  • Regional loss of SAT
  • Primarily in children and adolescents
  • Starting at the face and extending to the waist, sparing the legs
  • SAT may be increased on the legs
  • Because of the higher amount of SAT in the legs compared to the upper body
    • APL could be confused with the RAD, lipedema
  • APL is thought to be autoimmune
    • Occurring after a febrile (viral) illness
    • With low levels of complement factor 3 (C3)
    • Presence of a circulating autoantibody called complement 3-nephritic factor

Dif. dg. lipedem

  • Increased fat on the legs but the fat of the upper body is normal or increased

Treatment

Thiazolidinedione, rosiglitazone

  • Improved levels of C3
  • Increased SAT in a participant with APL

Cell-cycle mitoticpathways



Diuretics

  • Can quickly deplete lymphedema fluid
  • But concentrate protein in edematous tissue promoting fibrosclerosis
  • Use of diuretics in lipedema before lymphedema
    • May result in the development of pseudo Barrter's syndrome characterized by
      • Hypokalemic-hypochloremic alkalosis
      • Hyperactivity of the renin-angiotensin-aldosterone system
      • Elevation of atrial natriuretic peptide
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Idiopathic edema (IE)

  • Similar to lipedema by description
  • Identified in women with lipedema

Inhibition of Th2 differentiation

  • Reduces fibrosis,
  • Enhances lymphatic function,
  • Slows lymphedema progression
  • Biomedicines 2022, 10, 3081

PF4—a

  • Plasma-circulating exosomal signature
  • Protein—may be employed as a promising novel biomarker in clinical settings to diagnose lymphatic vasculature failure
  • Differentiation of lipedema and lymphedema from obesity
  • Lipedema patients had higher PF4 concentrations in blood-plasma-derived circulating exosomes
  • Expression of PF4 was likewise elevated in both young and old PROX-1+/- mice
    • Not in ob/ob mice (nonlymphatic promoted obesity).
  • PF4 might be a new biomarker for lymphatic diseases, including lipedema
  • PF4 is secreted by platelets upon activation during wound healing and inflammation
  • PF4 downregulates proteins associated with the tight junction
    • Increases cell permeability
  • PF4 may play a potential role in lymphatic disorders
    • Making the blood vessels more permeable
    • Decreasing lymphangiogenesis
  • PF4 also increases T helper 2 (Th2) cytokines
  • Causes the chemotaxis of T cells in a CXCR3-dependent manner
  • T cells (especially Th2 cells) penetrate lymphedematous tissue and contribute to inflammation, fibrosis, and lymphangiogenesis
  • Inhibition of Th2 differentiation
    • Reduces fibrosis,
    • Enhances lymphatic function,
    • Slows lymphedema progression
  • www.mdpi.com/2227-9059/10/12/3081

Progesterone

  • In rats
    • Has been reported to nullify the weight-reducing effects of estradiol
  • In women, higher progesterone levels in pregnancy
    • Correlated with weight gain
  • Progesterone is converted into its inactive form, 20-hydroxyprogesterone, by AKR1C1
    • Playing a role in the fat accumulation of the subcutaneous depot

Partial loss-of-function of AKR1C1

  • Negative effect on the conversion of progesterone to 20-?-hydroxyprogesterone
    • Thus potentially contributing to more weight gain
  • Biomedicines 2022, 10, 3081

Increased expression of VEGF-C

  • In the serum of lipedema patients was confirmed
  • Siems et al., this study did not show any differences in the levels of VEGF-D and VEGF-A
  • Increase in VEGF-C expression was not linked to any visible changes at the morphological level for lipedema
  • Higher expression of VEGF-C in lymphedema is shown to be linked to lymphatic remodeling
  • Biomedicines 2022, 10, 3081

VEGFR-3

  • Elevated (1.9-fold)
  • Other lymphatic-related genes were similar in to healthy controls
    • Podoplanin (PDPN), PROX-1, lymphatic-vessel endothelial hyaluronan receptor 1 (LYVE1),
    • C-C motif chemokine ligand 21 (CCL21)
  • Biomedicines 2022, 10, 3081
  • Inflammatory marker
  • Contributing to adipose insulin resistance by recruiting inflammatory macrophages
  • Activation of VEGFR-3 in lymphatic endothelial cells promotes the formation of lymphangiogenesis
    • Within and around tumors and facilitates metastasis [209].
  • Biomedicines 2022, 10, 3081



2x increase in VEGF-A expression

  • In the blood samples of lipedema patients
    • Increased angiogenesis and capillary fragility
  • estrogen plays a regulatory role in VEGF-A in AT

3T3-L1 cells

  • 17-beta estradiol (E2)
  • estrogen receptor 1 (ESR1) agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT)
  • Induced VEGF-A expression
    • By binding to hypoxia-inducible factor 1 alpha subunit (HIF1A) in the VEGF-A gene promoter

Impairment of estrogen signaling

  • May also be a culprit in the lymphatic dysfunction in lipedema
  • Biomedicines 2022, 10, 3081

AKR1C1

  • Can distinguish the lipedema condition from other lipid disorders,
  • Biomedicines 2022, 10, 3081

Acquired partial lipodystrophy (APL; BARRAQUER-SIMONS syndrome)

  • By a regional loss of SAT primarily in children and adolescents
    • Starting at the face and extending to the waist, sparing the legs
  • In fact SAT may be increased on the legs
  • APL is thought to be autoimmune
    • Occurring after a febrile (viral) illness
    • With low levels of complement factor 3 (C3)
  • Presence of a circulating autoantibody called complement 3-nephritic factor
  • Treatment with the thiazolidinedione, rosiglitazone
    • Improved levels of C3 and increased SAT in a participant with APL
  • APL could be confused with the RAD, lipedema
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/
  • Regional loss of SAT
  • Primarily in children and adolescents
  • Starting at the face
  • Extending to the waist
  • Sparing the legs
  • May be increased on the legs
    • Could be confused with the RAD, lipedema
  • APL is thought to be autoimmune occurring after a febrile (viral) illness
  • With low levels of complement factor 3 (C3)
  • Presence of a circulating autoantibody called complement 3-nephritic factor
  • C3 level<16.1 mg/dL (normal range: 90-180)
  • C4 level 23.11 mg/dL (normal range: 10-40)
  • Loss of SAT from the upper body to the waist but obesity of the hips and legs

Treatment with the thiazolidinedione, rosiglitazone


Increase in the adipogenic differentiation potential of lipedema

  • Main adipogenic gene markers: adiponectin, LPL, CD36, Leptin, PPAR and Glut4
      • PPAR gene expression showed a significant increase in differentiated adipocytes from lipedema
        • Demonstrated to regulate insulin sensitivity
  • Lipedema adipose tissue is highly infiltrated with immune cells
    • Increase in fibrosis and angiogenesis
    • Increased levels of macrophages observed around blood vessels
    • Forming crown-like structures surrounding necrotic adipocytes
  • Trend of increase in the gene expression of
    • VEGF, IL-6, IL-1beta and TNFalpha in adipocytes differentiated from lipedema
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7072543/

Consumed alcohol


Higher expression of aromatase (CYP19A1)

  • Responsible for the conversion of androgens to estrogen—in lipedema
    • Compared to lean healthy control tAT and the abdominal AT of the same lipedema patient
  • estrogen-receptor gene-expression
    • Unaffected in lipedema

ZNF423 expression

  • Zvýšená by estrogen in Ca prsu
  • Up-regulated in lipedema
  • ZNF423 expression in preadipocytes related to
    • Activation of PPARG
    • Directly to the maturation of adipocytes
  • Upregulation of ZNF423 is a potential mechanism by which estrogen promotes hyperproliferation in lipedema.
  • Biomedicines 2022, 10, 3081

Artificial colors

  • Some studies have suggested that the consumption of artificial colors may be associated with an increased risk of developing lipoedema.
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Bisphenols (BPA)

  • Industrial chemical used to make certain plastics
  • Linked to obesity
  • May increase the risk of developing lipoedema.
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Bisphenol A (BPA)

  • Industrial chemical that is commonly used to make certain plastics,
  • Found to have weak estrogenic activity.
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Bisphenol S (BPS)

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Bolest

  • Patients with lipedema experienced higher levels of pain (p < 0.001) and more significant pain-related disability in daily activities (p < 0.001) than controls. Correlation analysis among patients with lipedema showed a positive correlation between pain severity and depressive symptoms (? = 0.612, p < 0.001) and a moderate positive correlation with impaired health-related quality of life (? = 0.418, p = 0.010).
  • www.mdpi.com/2075-1729/14/3/295

CD11c (ITGAX)

  • Marker gene for immune-cell infiltration
  • T-cell activation and accumulation in AT
  • Leading to insulin resistance in obesity
  • Increased in lipedema
  • Biomedicines 2022, 10, 3081

CD31, a vascular endothelial marker

  • Significant increase detected in SVF-T and SVF-A isolated from lipedema
  • Increase in the endothelial/pericytic marker CD146 in SVF isolated from the hips and thigh
    • Might be a marker of repair of leaky blood and lymphatic vessels in lipedema tissues
  • no difference in the MSC markers CD90, CD73 and CD105
    • Contradicts the data published by Bauer et al. showing a significant increase in proliferation in lipedema ASCs at day 14
    • In contrast to Priglinger et al. and Bauer et al., we showed a significant increase in the adipogenic potential of ASCs-T of lipedema patients
  • Different :
    • Techniques used to perform the proliferation and differentiation assay
    • Different liposuction techniques
    • Disease stage of the patients enrolled in the study.
  • Lipedema and healthy ASCs isolated from two diverse depots of adipose tissue display a distinctive clonogenic and differentiation potential toward adipogenic and osteogenic lineages
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC7072543/

Perfluorinated compounds (PFCs)

  • Used in a variety of industrial and consumer products, such as non-stick cookware
  • Weak estrogenic activity.
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Dichlorodiphenyltrichloroethane (DDT)

  • Pesticide that was widely used in the past
  • Weak estrogenic activity.
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Tributyltin (TBT)

  • Used as an antifouling agent in marine paints
  • Has weak estrogenic activity.
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Benzo[a]pyrene

  • In tobacco smoke and certain types of coal tar
  • Carcinogen
  • Has weak estrogenic activity.
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Styrene

  • Chemical used in the production of plastics and rubber
  • Possible human carcinogen
  • Weak estrogenic activity.
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Alkylphenols

  • Chemicals used in the production of cleaning products, pesticides, and personal care products
  • Weak estrogenic activity.
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Di-n-butyl phthalate (DBP)

  • Production of PVC plastics
  • Weak estrogenic activity.
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Di(2-ethylhexyl) phthalate (DEHP)

  • Production of PVC plastics
  • Weak estrogenic activity.
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Coffee

  • Caffeine, which is a stimulant
    • Can affect the central nervous system.
  • Some studies have suggested that coffee consumption may be associated with an increased risk of developing lipoedema
    • Although more research is needed to confirm the link and to understand the underlying mechanisms.

A study published in the Journal of Lipoedema

  • Women with lipoedema who consumed more than two cups of coffee per day had a higher risk of developing the condition compared to those who consumed less.

Another study published in the Journal of Lipoedema

  • Women with lipoedema who consumed more than two cups of coffee per day had a higher risk of developing the condition compared to those who consumed less.

Chocolate

  • High in calories and fat, and it's been linked to weight gain which may increase the risk of developing lipoedema.

A study published in the Journal of Lipoedema

  • Women with lipoedema who consumed more chocolate had a higher risk of developing the condition compared to those who consumed less.

Another study published in the Journal of Lipoedema

  • Women with lipoedema who consumed more chocolate had a higher risk of developing the condition compared to those who consumed less.
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Connective tissue disorder

  • Loss of elastic recoil in adipose tissue
  • Fluid to collect rather than exit into lymphatics
  • Loss of recoil is seen when dye is injected into lipedema tissue
    • Instead of forming a small rounded spot before entering lymphatics
    • Dye seeps into the tissue forming flame-like structures [7]

Other connective tissue mutations

  • [7]

Cortizol

  • Triggered by an extremely stressful situation
    • Death in the family
    • Divorce

Corticosteroids

  • Produce a fast reduction in swelling and pain
  • But increase the risk of infection, capillary fragility and SAT growth
  • A series of corticosteroid joint injections is usually well-tolerated without exacerbation of lipedema
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Cytokines

  • 22 cytokines were found in lipedema serum
  • IL-11, IL-28 A, and IL-29 were increased in the sera of lipedema patients
  • IL-29
    • Implicated in the pathogenesis of obesity-induced inflammation
    • Insulin resistance by upregulating the expression of
      • IL-8,
      • Interleukin-1 beta (IL-1beta),
      • Monocyte chemoattractant protein-1 (MCP-1)
  • IL-28A and IL-29 - secreted by macrophages
  • IL-11
    • Promote cellular proliferation in ADSCs
    • Inhibit adipogenesis in a murine fibroblast cell line
      • Hyperplasia seen in lipedema ADSCs
  • Biomedicines 2022, 10, 3081

Depression and anxiety



Dercum's disease (DD) - (adiposis dolorosa; Morbus Dercums)

Diagnosis of DD

  • Primarily in women
    • Females to males of 5-7:1186
  • Suggesting a hormonal component
  • Painful SAT

Cardinal and accessory signs and symptoms of Dercum's disease

  • Fat deposits Nodules (lipomas) in fat ranging in size from rice grains to a fist or larger
  • Pain in fat deposits for at least 3 months
  • Pain exacerbated by stress, strenuous exercise, trauma, changes in weather
  • Pain can be spontaneous or on palpation; may wax and wane or move around
  • Fatigue (asthenia) Exacerbated by activities of daily living or exercise
  • Cognitive change(s) Memory difficulties;
  • Difficulty forming thoughts; “brain fog”
  • Weight gain
  • Difficult to lose fatty deposits with lifestyle changes
  • Vascular involvement
  • Visible vascularity near lipomas; telangiectasias; multiple cherry angiomas, multiple petechiae; easy bruising; flushing; hematuria of unknown etiology; heavy or prolonged menstrual bleeding; epistaxis
  • SAT edema Non-pitting
  • Gastroesophageal reflux disease, irritable bowel syndrome, bloating, abdominal pain, early satiety
  • Joint pain and/or stiffness
  • Increased in areas of fat deposits
  • Muscle pain/stiffness Especially on awakening or the day after physical activity
  • Shortness of breath In the presence of normal oxygen saturation or as part of the need for oxygen supplementation
  • Tachycardia Varies from palpitations to supraventricular tachycardia requiring beta-blockade
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Type I, juxta-articular (around the joint)

  • Painful folds or nodular fat on the inside of the knees and/or on the hips
  • In rare cases only evident in the upper-arm fat (similar to Type IV lipedema).
  • Painful lumps of fat first noticed around joints in DD Type 1
    • Occur in locations of lymph nodes, for example
      • Around the knee (popliteal nodes),
      • The elbow (cubit nodes),
      • Hips and thighs (inguinal nodes),
      • Upper arm (axillary nodes)
      • Supraclavicular
  • As Dr Kling reported in 112 cases of Type I DD, “Juxta-articular adiposis dolorosa
    • Regarded as the initial and intermediate stage of generalized adiposis dolorosa”
  • Dercum's disease Type I is therefore, the first stage of DD
  • Type I DD around the knees is visually consistent with Type IV and Type II lipedema Stages 2–3.

Type II, diffuse, generalized type

  • Widespread pain from fatty tissue found anywhere from head to the soles of the feet.
  • Type II a stage with more widespread dysfunction

Type III, nodular type

  • Intense pain in and around multiple “lipomas”, sometimes in the absence of obesity.
  • Type III DD is likely a variant of familial multiple lipomatosis (FML)
    • Men present mainly with lipomas and/or angiolipomas
      • Predominating on the lower and upper arms
      • Lower trunk and thighs
    • Women present with lipomas, angiolipomas and obesity
  • Angiolipomas can be found in up to 30% of people with DD
  • The lipomas are generally not painful in FML
    • Except if they are growing or traumatized frequently
    • They are painful in DD Type 3.
  • At some point in time a lipoma can become painful
    • Followed by generalized pain in all lipomas
      • Lipoma dolorosa, distinct from DD
  • “local conditions”
    • May be increased tissue tension from fluid accumulation
  • In two cases of DD Type III
    • Pain was relieved after local hemorrhage
  • DD inheritance Thought to be autosomal domin-ant
  • Females were more affected than males
  • Dr Dercum and others found an infiltration of nerves (neuritis)
  • Increased connective tissue around nerves, blood vessels and as thickened septae has been noted
  • Perivascular cells, granulomas suggestive of a foreign body reaction are apparent in some areas

DD asscoiated problems:

  • Thyroid dysfunction
  • Pituitary dysfunction
  • Polyglandular disease
  • Infection
  • Neuritis,
  • Alcohol,
  • Trauma,
  • Defect in the synthesis of long chain fatty acids
  • Lower resting energy expenditure
  • Altered responses to norepinephrine and insulin
  • “chronic intoxication of endogenous origin”
  • Vascular dysfunction as hematemesis
  • Epis-taxis
  • Hemaochezia
  • Heavy menses
  • Varicose veins
  • Altered vasoconstrictor responses
  • Common in both lipedema and DD
  • Perivascular infiltration of immune cells in DD tissue
    • Damage to or repair of blood vessels, and brain vasculitis in DD has been reported
  • Fibrosis secondary to lymphedema222 is common in lipedema112 and DD202.
  • Presence of lymphatic and vascular dysfunction in lipedema, the fat is painful, similar to DD.
  • Original descriptions of DD match descriptions of lipedema
  • Hemolymph nodes
    • Structures resembling a lymph node, but which can have blood in the sinuses
    • Erythrocytes enter the hemolymph nodes through afferent lymphatics
    • Few reports on the function of hemolymph glands in humans.
  • Vascular and lymph system are dysfunctional in both lipedema and DD
    • Pre-lymph remains in the tissue longer
      • Inducing fat growth and the characteristic beans in a bag feel to the fat
  • estrogen and/or progesterone likely play a role
    • DD with menopause
  • In DD, a more widespread insult to the vascular and lymphatic system may occur compared to lipedema
  • Asthenia (abnormal physical weakness or lack of energy)
  • Psychiatric, motor, sensory and sympathetic nervous systems
  • Pulmonary, endocrine, gastrointestinal and rheumatological systems .
  • Thyroid dysfunction as one etiology of DD
    • Few cases of DD benefited from thyroid treatment
    • Many cases of DD failed to improve
    • DD generally continues to progress during adequate thyroid replacement
  • Multiple endocrine dysfunction as a cause for DD
    • But ACTH and pituitary extract did not improve signs and symptoms associated with DD
    • Hormone testing was normal in other cases
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/


4391 significant differences in the mRNA expression

  • Such as lipid metabolism and proliferation/cell cycle, in lipedema tissue
  • Gene-expression profile favored
    • Adipose hyperproliferation,
    • Fibrosis,
    • Inflammation
  • Features observed in lipedema
  • Biomedicines 2022, 10, 3081

Dioxins

  • Chemicals that are produced through industrial processes
  • Can have weak estrogenic activity.
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Diuretics

  • Can quickly deplete lymphedema fluid
  • Concentrate protein in edematous tissue promoting fibrosclerosis
  • Use of diuretics in lipedema before lymphedema may result in the development of pseudo Barrter's syndrome
    • Characterized by hypokalemic-hypochloremic alkalosis
    • Hyperactivity of the renin-angiotensin-aldosterone system
    • Elevation of atrial natriuretic peptide
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/


Drugs to Avoid with Lipedema

Diuretics

Thiazolidnediones

  • Rosiglitazone
  • Pioglitazone
  • Increases fat tissue

Impairment of Endothelial Junction + Increased Permeability of Endothelial Cells

  • Insufficient backflow
    • Leading to excess fluid accumulated in the interstitium
      • Associated with adipocyte hypertrophy and hyperplasia
        • Leading to hypoxia, microangiopathy, and a higher permeability
  • Microangiopathy in tAT (not the abdomen) for lipedema has been confirmed
    • Dysregulated endothelial function leads to the excessive growth of fat
      • Leading to necrosis, inflammation, and fibrosis

Primary human endothelial cells (hECs) treated with lipedema SVF-derived conditioned media (CM)

  • Weakened endothelial junctions, markedly increased endothelial permeability,
  • Significant decrease in the expression of Cadherin 5/VE-cadherin (CDH5)
  • Slightly decreased expression of ZO-1 (a component of the endothelial tight junction) was observed
  • no difference in the expression of E-selectin and TIE-2
  • Relative gene expression of TIE-2 was downregulated
    • TIE-2 activation by its ligand, angiopoietin-1 (ANGPT-1)
      • Supports vascular maintenance by forming a tightened barrier
      • Activation of TIE-2 reorganizes the actin cytoskeleton and accumulates CDH5 at the endothelial junction
      • Functions of CDH5 and TIE-2 seem to be intricately connected, leading to a tightened endothelial junction

Estrogen a histamin - jeden z možných projevů alergie

Ženy

  • In women, if allergy symptoms increase in the middle of the menstrual cycle
    • It is likely that estrogen is contributing to the problem.

Muži

  • estrogen levels increase as they age
    • Formation of breast tissue (gynecomastia)
  • If their allergy symptoms increase as they age
    • estrogen is most likely a contributing factor.

Estrogenní dominance

  • Too much estrogen relative to progesterone
    • Not enough progesterone to oppose estrogen

Symptoms of estrogen dominance can include:

  • Irritability
  • PMS
  • Weight gain
  • Heavy periods
  • Painful periods
  • Fibrocystic breasts
  • Fibroids
  • Endometrial hyperplasia
  • Water retention
  • Breast tenderness or fibrocystic breasts
  • Bloating before your period
  • Weight gain on your hips, butt, or thighs
  • Endometriosis
  • Adenomyosis 
  • Perimenopause
  • Menopause
  • Hair loss, or hair popping up where you don’t want it
  • estrogen can look normal in labs
    • But the metabolites that are produced in the liver can be problematic
  • PMS could be due to estrogen dominance.
  • Heavy periods, tender breasts, mood swings, hot flashes and water retention
    • High chance that you are estrogen dominant

Více o faktorech přispívajících k estrogenní domenanci / inhibici zde




Ethinylestradiol

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Familial partial lipodystrophies (FPLD)

FPLD Type 1 - Köbberling lipodystrophy

  • Mutations in the lamin A and C gene, LMNA, cause FPLD
  • Partial lipodystrophy primarily found in women
  • Arms, legs, and sometimes breasts
  • Increase in fat on the abdomen and remainder of the trunk
  • no blood or urine biomarkers for FPLD1
  • SAT ends on the buttocks
  • Diabetes and hypertriglyceridemia are highly prevalent in FPLD1
  • Acanthosis nigricans is minimal

FPLD Type 2 - Dunnigan lipodystrophy

  • Mutations in the lamin A and C gene, LMNA, cause FPLD
  • SAT is lost around the time of puberty from the legs, arms, buttocks, abdomen and chest;
    • Areas of remaining SAT deposits are on the back, face and chin,
      • Giving a Cushingoid appearance
    • fat is increased in the labia majora in women
      • Also occurs in women with MSL
  • Leptin levels can be very low in lipodystrophies

Leptin treatment

  • Has shown benefit but remains investigational

RYGB

  • Has also shown benefit in reducing the co-morbidities associated with FPLD227.

FPLD Type 3 - FPLD329 obesity

  • Mutations in the peroxisome proliferator-activated receptor gamma (PPARG) gene
  • Can cause partial lipodystrophy with abdominal obesity
  • May look very similar to FPLD2

Thiazolidinediones


Fibronectin-1 (FN-1) knockout

  • Failure of fibronectin fibrillogenesis
  • Promote the intermolecular interactions needed for fibril formation, a critical determinant of adipogenesis
  • In lipedema, as a lower expression of FN has been confirmed
    • Failure to undergo fibrillogenesis may be an underlying cause of impaired adipogenesis
  • Biomedicines 2022, 10, 3081

High Fructose Corn Syrup (HFCS)

  • Sweetener commonly found in processed foods and drinks
  • Linked to weight gain, which may increase the risk of developing lipoedema.
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Phthalates

  • Commonly used to make plastics more flexible
  • Can have weak estrogenic activity.
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Neuronal guanine nucleotide exchange factor (NGEF)

  • Known role linked to abdominal obesity
  • Genes found to be altered
  • Biomedicines 2022, 10, 3081

F-box/LRR-repeat protein 7 (FBXL7)

  • Linked to metabolic syndrome
  • Modified response to corticosteroids,
  • Genes found to be altered
  • Biomedicines 2022, 10, 3081

Variant (c.638T > A; p. Leu213G1n) in aldo-keto reductase family 1 member C1 (AKR1C1)

  • In the SAT of three affected females of the family
  • AKR1C1 gene involved in progesterone metabolism
  • Higher expression has been established in the SAT of obese women
  • Biomedicines 2022, 10, 3081

GH deficiency

  • Increase in fat mass
  • GH treatment in children and adults with GH deficiency reduces abdominal fat mass
  • Decreases fat-cell size
  • Secretion of GH is also sex-dependent
  • Three times higher secretion in women compared to men
  • Biomedicines 2022, 10, 3081

Monosodium Glutamate (MSG)

  • Flavor enhancer that is commonly found in processed foods
  • Linked to obesity, which may increase the risk of developing lipoedema.
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Human immunodeficiency virus (HIV)-associated lipodystrophy

  • HIV-and highly active antiretroviral treatment (HAART)-associated lipodystrophy
  • In men with lipodystrophy, SAT can be increased
    • Abdomen and chest (gynecomastia)
    • Dorsocervical fat pad or “buffalo hump” - identical to the SAT in multiple symmetric lipomatosis (MSL)

Inzulinová rezistence in HIV+ men1

  • Parotid hypertrophy,
  • Circumferential enlargement of the neck
  • Dorsocervical fat
  • Intermuscular fat and SAT on the legs in HIV+ women
  • Large breasts are part of HIV lipodystrophy in Black women and other non-Caucasian ethnicities
  • Women with HIV may also develop increased SAT on the upper part of the arm
    • Out of context with the usual lipoatrophy
  • Upper arm SAT looks visually similar to the SAT in women with the RAD, MSL
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Multiple symmetric lipomatosis non-HIV-related MSL Type II


Hormonal change

  • Childbirth
  • Menopause
  • HAK
  • Predominant occurrence of lipedema in females
  • Importance of sex hormones in the development
  • Distribution of lipedema fat is in the female gynoid distribution
    • Disproportion between the upper and lower body with
      • Waist to hip ratio <1
  • Lipedema fat on the arms
    • In 80% of women with lipedema
    • Gynoid distribution of lipedema fat dominates [7]

Femal hormons

  • Appears to be related to estrogen and progesterone hormonal influences
  • Occurs largely in females
  • Worsens in connection to hormonal occasions

Hypoxie

  • Lipedema adipose tissue is a highly vascularized and fibrotic tissue
  • Increase in blood vessels
  • Infiltrating macrophages
  • Hypertrophic adipocytes
  • Increase in the proliferation of adipose-derived stem/progenitor/stromal cells (Ki67+ and CD34+ cells)
    • Increase in adipogenesis
    • Tissue hypoxia,
      • Adipocyte necrosis and macrophage infiltration
  • Adipose-derived stromal/stem cells (ASCs) obtained from lipoaspirates
    • Increase in the number of CD146+ endothelial/pericytic cells in lipedema
      • Might be a marker of leaky blood and lymphatic vessels in lipedema adipose tissue
  • Biomedicines 2022, 10, 3081

Inzulin

  • Lipohypertrofie
    • V místech po vpichu inzulínu u něktetrých lidí

Excessive collagen deposition

  • Form of ECM remodeling
  • Observed in lipedema
  • Deposition of collagen is under the tight control of matrix metalloproteinases (MMPs)
    • Expressed similarly in both lipedema and healthy spheroids, except for MMP11
      • Showed a (nonsignificant) decreased expression
  • Dysregulation of MMP11 expression was previously established early in AT dysfunction in obesity

Slight decrease in MMP11 expression in lipedema

  • May contribute to excess collagen deposition
  • MMP11 is known to cleave COL6A3
  • Reducing collagen deposition
  • Biomedicines 2022, 10, 3081

Corticosteroids (oral):



Aluminum, cadmium, copper, cobalt, nickel, lead, tin, and chromium

  • Samozřejmě, že prsní žláza jako žláza moc ráda vychytává ionty (třeba jodu), když vychytá špatné ionty, je vymalováno....nebo spíš zoxidováno.

Kovy jako pravděpodobná negentická příčina / silný rizikový faktor / Ca prsu

  • Direct and positive association between Cd and Ni concentrations and BC risk. It is a warning to health care providers and policy makers to find viable solutions and take requisite measures to reduce BC risk in the society.
  • www.spandidos-publications.com/10.3892/ol.2019.11206

Arsenic (As), cadmium (cd), chromium (Cr), lead and mercury


Blood-vessel capillaries hyperpermeable

  • Extra fluid enters the interstitial space
  • The more dilated blood microvessels in lipedema
    • More fluid to the ECM
  • Dilated venules that cause capillary leakage
    • Dysregulated vascular function in lipedema SAT
      • Resulting in vascular sclerosis, IF accumulation, and the deposition of fibrotic materials
  • Biomedicines 2022, 10, 3081


Leaky vessels and consequent immune-cell recruitment and inflammation

  • Associated with lipedema
  • Only surface markers elevated in freshly isolated lipedema were
    • CD90 (mesenchymal) (12% higher)
    • CD146 (endothelial) ( 20% higher)
    • Which is highly expressed in subcutaneous ADSCs
      • Essential for AKT activation and CCND1 upregulation
        • Regulating cell growth and differentiation
  • An elevated expression of CD90
    • Might be related to the hyperplasia seen in lipedema
  • CD146
    • Endothelial/pericyte marker - receptor for angiopoietin-like protein 2 (ANGPTL2)
    • Implicated in promoting obesity by enhancing adipogenesis and lipogenesis
  • Biomedicines 2022, 10, 3081

Leptin

  • Believed that the hormone leptin could be the key hormone in the dysregulation of fat deposition and distribution [1]

Leptin and PPAR gamma zvýšená exprese na adipocytech

  • Is a painful loose connective tissue disorder
  • Bilaterally symmetrical fat deposition in the lower extremities

40 patients, 20 healthy and 20 with lipedema

  • Similar expression of mesenchymal markers
  • Significant increase in colonies (p < 0.05)
  • no change in the proliferation rate in ASCs isolated from the SVF-T or SVF-A of lipedema patients compared with healthy
  • Leptin gene expression was significantly increased in lipedema adipocytes differentiated from ASCs-T (p = 0.04)
  • PPAR-gamma expression was significantly increased in lipedema adipocytes differentiated from ASCs-A (p = 0.03)
  • No significant changes in the expression of genes associated with inflammation were detected in lipedema
  • Lipedema ASCs isolated from SVF-T and SVF-A have a higher adipogenic differentiation potential compared to healthy ASCs.
  • Biomedicines 2022, 10, 3081

Altered Lipid Composition in Lipedema

  • Number of fat droplets per cell was significantly increased in lipedema adipocytes
  • Liquid chromatography–mass spectrometry (LC-MS)
    • 928 lipid species total
    • 112 were found to be significantly altered in lipedema
  • Significantly increased lipids in lipedema included
    • Glycerophospholipids (GPLs),
    • LPE (24:1), PC (28:2), PC (26:0), PE (42:2), PE (42:1), LysoPC (24:1), and PC [ 24 ]
  • Higher proportions of glycerophospholipids and sphingolipids found in lipedema
    • Implicated in the metabolic dysfunction of AT
  • ceramide synthase 6-derived C16:0 sphingolipids
  • Oily phase of the lipoaspirate and serum of lipedema patients by mass spectroscopy
    • Difference in the lipid profile
    • Lipedema decreased lysophosphatidylcholine in plasma
    • Higher levels of cyclopropane-type fatty acids and inflammatory mediators in the oil phase of lipoaspirates
  • 640 distinct metabolites were identified in lipedema adipocytes
    • Highest metabolite classes belonging to amino acid and carbohydrate metabolism
      • lysine biosynthesis
      • Glutamate metabolism !!!
      • Glucagon-like peptides (GLPs)
  • Biomedicines 2022, 10, 3081

Total cholesterol

  • (1.31-fold) in lipedema patients
  • Primarily obtained from lipedema patients in stage III of the disease
  • Biomedicines 2022, 10, 3081

Triglycerides

  • (1.49-fold) in lipedema patients
  • Primarily obtained from lipedema patients in stage III of the disease
  • Biomedicines 2022, 10, 3081

Low-density lipoprotein

  • (LDL; 1.46-fold)
  • LDL and ApoB are directly correlated
  • Primarily obtained from lipedema patients in stage III of the disease
  • Biomedicines 2022, 10, 3081

ApoB

  • (1.37-fold) in lipedema patients
  • LDL and ApoB are directly correlated
  • Ratio of LDL/ApoB is related to the LDL particle diameter
    • As ApoB is a carrier of LDL
    • Higher values usually signify a risk for cardiovascular disease
  • Increase in ApoB values was found in lipedema serum
  • Primarily obtained from lipedema patients in stage III of the disease
  • Biomedicines 2022, 10, 3081

High-density lipoprotein (HDL) and associated ApoA

  • Were comparable between lipedema and control groups
  • Primarily obtained from lipedema patients in stage III of the disease
  • Biomedicines 2022, 10, 3081

Association of lipedema tissue with loss of elasticity

  • Supports lipedema as a connective tissue disorder [7]

Lipoedema in men

  • Men with lipedema have been reported in the literature only as case reports
  • Tend to have conditions associated with
  • Such as
    • Male hypogonadism
    • Liver disease [7]

Lymfostáza

  • Lymph placed on adipocytes in culture
    • Also induces robust growth
  • “lymph makes you fat”
  • Kaposi-Stemmer sign is negative in lipedema (the skin cannot be pinched as a fold by the fingers) until the development of lipolymphedema
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Significant increases in macrophage infiltration in lipedema

  • CD45- and CD68-positive cells
  • Due to increased expression of vascular endothelial growth factor receptor 3 (VEGFR-3)
    • Well-known to be present in macrophages
    • M2 phenotype due to the overexpression of CD163
      • Scavenger receptor might indicate the presence of a compromised endothelial barrier
  • Decreased expression of KLF4
    • Similar to CD163, is a marker of M2-polarized macrophages
      • Promotes this phenotype and inhibits M1 polarization
  • M1 macrophages are usually associated with the inflammatory phenotype
    • Higher expression in AT has been reported in obesity
  • M2-polarized macrophages
    • Associated with angiogenesis in preadipocytes
    • Overabundance in aberrant fibrogenesis
  • Macrophages have been confirmed to be drivers of the inflammatory phenotype in lipedema
  • Reduced levels of IL-8—a proinflammatory cytokine—may be explained by higher levels of estrogen
  • Expression level of VEGFR-3 has been found to increase
    • With the decreased expression of vascular endothelial growth factor A (VEGF-A)
    • Vascular endothelial growth factor D (VEGF-D) in the AT of lipedema patients
  • Biomedicines 2022, 10, 3081

Infiltration of M2 macrophages

  • Confirmed in lipedema
  • M1 macrophages, aerobic glycolysis is induced upon activation
    • Increase in glucose uptake and the conversion of pyruvate to lactate
    • Respiratory chain are reduced
      • Allowing for reactive oxygen species production
  • M2 macrophages
    • Energy from fatty acid oxidation and oxidative metabolism
    • Under the IL-4 activation of M2 macrophages, STAT6 induces PPARG coactivator-1B (PGC1B)
  • PGC1B
    • Together with other TFs, nuclear factor 1 (NRF-1), and estrogenrelated receptor alpha (ERRa)
      • Drives the production of critical mitochondrial components,
        • Cytochrome c and ATP
    • Is a crucial driver of higher oxidative capacity in M2 macrophages
    • Acts as a metabolic switch
    • Lack of function leading to the M1 phenotype.
  • Growth-differentiation factor 15 (GDF15)
    • Induces the polarization of macrophages to the M2 phenotype
      • By upregulating the oxidative function
  • Higher oxidative metabolic capacity in lipedema SVF (at least partly)
    • Correlates with the phenotype macrophages present in lipedema
  • Biomedicines 2022, 10, 3081

Mechanické změny ve tkáních

  • Excess fat physically impedes lymph collection and flow,
  • protein-rich lymphatic fluid collects in SAT,
  • Resulting in lymphedema and tissue hypoxia
  • SAT also grows in the presence of lymphedema
  • Accumulation of fluid in the setting of decreased oxygen tension leads to fibrosis
  • Ischemia activates the growth of adipose-derived progenitor cells
  • Congestion of lymph nodes by other means, such as lymphoma in the neck
    • Induces fat growth similar to MSL
  • Increased volumes of SAT in MSL, like obesity,
    • May therefore be sufficient to externally compress vasculature and lymphatics
      • Inducing further growth of SAT as seen in other localized fat collections
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

miR-16-5p

  • Significantly upregulated during differentiation of 3T3-L1 preadipocytes
    • By regulating EPT1 gene expression
  • Role in inhibiting cell proliferation through the regulation of cyclin genes
    • Including CCND1, which have already been shown to be highly expressed in lipedema AT
  • Decreased
  • Biomedicines 2022, 10, 3081

Micro-RNAs

  • Total of 187 extracellular miRNAs were analyzed
  • SEV miRNAs (miR-16-5p, miR-29a-3p, miR-24-3p, miR-454-p, miR-130-3p, and let-7c-5p)
    • Differently expressed in lipedema
    • Only one (miR-188-5p) in healthy tissue
  • Some of these micro-RNAs
    • Implicated in various dysregulations of AT - not unique or specific to lipedema
  • Altered miRNAs of EVs are essential for lipedema rather than the total RNA.
  • Biomedicines 2022, 10, 3081

Mitochondria from lipedema

  • Higher oxygen consumption rate than control
    • Lipedema SVF has an increased oxidative metabolic capacity
  • Biomedicines 2022, 10, 3081

Matrix metallopeptidase 14 (MMP14)–caveolin-1 (CAV-1) axis,

  • MMP14 and CAV-1 are mutually regulated through a feedback
  • Overexpression of MMP14 in this associated with
    • A hypertrophic phenotype in SAT
    • Decreased expression of the Prospero homeobox 1 (PROX-1) master regulator of the lymphatic system
    • Dysfunction of estrogen signaling
    • Increased permeability, and fragility of blood vessels
  • Biomedicines 2022, 10, 3081

Hormonal imbalances

Thyroid autoimmune disorders

  • Imbalances may contribute to the development of lipoedema
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Hashimoto's thyroiditis

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Graves' disease

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Inflammation

  • Inflammation of the fat cells in the affected areas
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Genetics

  • Lipoedema and thyroid autoimmune disorders are both thought to have a genetic component
    • Increase the risk of developing both conditions.
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Thyroid autoimmune disorders

  • Thought to involve an immune system dysfunction
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Lymphatic dysfunction

  • Lipoedema is often accompanied by lymphatic dysfunction
    • Can cause swelling and fluid accumulation in the affected areas

Some studies suggest that the lymphatic dysfunction observed in lipoedema

    • Might be related to the autoimmune dysfunction observed in thyroid autoimmune disorders.
  • More research is needed
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Insulin resistance

  • Body's cells do not respond properly to insulin
  • Insulin resistance can lead to the accumulation of fat in the affected areas.
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Adipocyte differentiation

  • Stem cells become mature fat cells
  • May be altered in people with lipoedema
    • Leading to the abnormal growth and accumulation of fat cells.
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Inflammation

  • Key role in the development of lipoedema
  • Causes the release of cytokines, which can stimulate the growth and differentiation of fat cells.
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Lipolysis altered

Some studies - may be altered in people with lipoedema

  • Leading to the abnormal accumulation of fat cells.
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Lymphatic dysfunction

  • Lipoedema is often accompanied by lymphatic dysfunction
    • Cause swelling and fluid accumulation in the affected areas
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Dermatan sulfate

Studies - association between lipoedema and increased levels of dermatan sulfate (DS) in the affected areas.

  • Increased levels of DS have been found to be related to the
    • Accumulation of fluid,
    • Presence of fibrosis,
    • Decrease in the elasticity of skin
  • Accumulation of DS
    • May contribute to the development of lipoedema
      • By altering the function of the lymphatic system.
  • Association between lipoedema and dermatan sulfate
    • Is still being researched
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Enzymes glycosaminoglycan synthases (GAGS)

  • Synthesis of DS is mediated by a family of enzymes called glycosaminoglycan synthases (GAGS)
    • Catalyze the formation of GAGs from simple sugars.
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Proteoglycans

  • Large molecules that consist of a core protein and one or more GAG chains
  • Synthesis of DS is often linked to the synthesis of proteoglycans
    • Required for the proper structure and function of connective tissues.
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Growth factors in the regulation of DS synthesis

Transforming growth factor beta (TGF-beta)

Fibroblast growth factor (FGF)

Platelet-derived growth factor (PDGF)

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Inflammation

  • Key driver of DS synthesis
  • Inflammation-associated cytokines that increase the production of DS
    • TNF-alpha
    • IL-1beta
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Estrogen and progesterone

  • Role in the regulation of DS synthesis
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Hyaluronan

  • Glycosaminoglycan that is closely related to DS
  • Stimulate the synthesis of DS in some cases.
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Matrix metalloproteinases (MMPs)

  • Enzymes that play a role in the degradation of extracellular matrix components, including DS

Some studies - suggested that MMPs may also play a role in the synthesis of DS.

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Insulin-like growth factors (IGFs)

  • Family of growth factors
  • Role in the regulation of cell growth and differentiation

Some studies - IGFs may also play a role in the synthesis of DS.

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Lipid mediators - prostaglandins and leukotrienes

  • Role in the regulation of DS synthesis.
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Lymphatic dysfunction

  • Lymphatic dysfunction can also lead to the accumulation of DS in the skin.
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Pregnancy or menopause

  • Can affect the accumulation of DS in the skin.
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Genetics

  • Genetic variations have been associated with an increased risk of DS accumulation in the skin.
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Trauma to the skin

  • Surgery or injury, can stimulate the accumulation of DS in the affected area.
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Lack of vitamin C and other antioxidants

  • Can affect the accumulation of DS in the skin.
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Vitamin D deficiency

  • Associated with an increased risk of DS accumulation in the skin.
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Zinc deficiency

  • Zinc is essential for the synthesis of DS
  • Deficiency in zinc can affect the accumulation of DS in the skin.
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Environmental toxins - lead and cadmium

  • Increased risk of DS accumulation in the skin.
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Smoking

  • Affect the accumulation of DS in the skin
    • Possibly due to the toxic chemicals present in tobacco smoke.
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Alcohol consumption

  • Linked with an increased risk of DS accumulation in the skin.
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Air pollution

  • Associated with an increased risk of DS accumulation in the skin.
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Copper deficiency

  • Copper is an essential mineral that is required for the synthesis of DS
  • Deficiency in copper can affect the accumulation of DS in the skin.
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Iron deficiency

  • Iron is an essential mineral that is required for the synthesis of DS
  • Iron deficiency can affect the accumulation of DS in the skin.
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Exposure to UV radiation

  • Prolonged exposure to UV radiation from the sun or tanning beds
    • Can affect the accumulation of DS in the skin.
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Exposure to heavy metals - lead and mercury

  • Can affect the accumulation of DS in the skin.
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Exposure to pesticides and herbicides

  • Affect the accumulation of DS in the skin.
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Lack of physical activity

  • Can lead to an accumulation of DS in the skin.
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Diet high in processed foods, sugar, and saturated fats

  • Can affect the accumulation of DS in the skin.
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Chronic stress

  • Can affect the accumulation of DS in the skin.
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Pregnancy or menopause

  • Can affect the accumulation of DS in the skin.
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Exposure to radiation, ionizing radiation, such as from X-rays or radiation therapy

  • Can affect the accumulation of DS in the skin.
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Lupus or rheumatoid arthritis

  • Can affect the accumulation of DS in the skin.
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Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Can affect the accumulation of DS in the skin.
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Pollution or industrial chemicals

  • Can affect the accumulation of DS in the skin.
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Streptococcal infections

  • Can affect the accumulation of DS in the skin.
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Microbiome in the gut or on the skin

  • May affect the accumulation of DS in the skin.
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Exposure to electromagnetic radiation

  • Such as from cell phones or Wi-Fi
    • May affect the accumulation of DS in the skin.
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Lack of sleep

  • Insufficient or poor quality sleep may affect the accumulation of DS in the skin.
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Genetic variations

  • May affect the accumulation of DS in the skin.
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Certain strains of probiotics

  • May be associated with a worse condition in people with lipoedema.
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Lymphatic dysfunction

  • Can also lead to the accumulation of bacteria and other microbes in the affected area.
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Microbiome

  • May have an imbalance in their gut microbiome.
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Nickel

  • Metal that is commonly found in the environment
  • Present in many common items such as coins, jewelry, and cell phones.
  • Exposure to nickel may be associated with an increased risk of developing lipoedema.

International Journal of Dermatology

  • Women with lipoedema had significantly higher levels of nickel in their blood compared to healthy controls.
  • This suggests that exposure to nickel may be a risk factor for the development of lipoedema.

Another study- nickel sensitivity

  • More prevalent in women with lipoedema than in the general population
  • Nickel may play a role in the development of the condition by causing inflammation and by interfering with the metabolism of fat.
  • More research is needed
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Phthalates

  • May be associated with an increased risk of developing lipoedema.
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Bisphenol-A (BPA)

  • May be associated with an increased risk of developing lipoedema.
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Parabens

  • Commonly used as preservatives in cosmetics and personal care products.

Studies - exposure to parabens

  • May be associated with an increased risk of developing lipoedema.
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Endocrine disruptors

  • Chemicals that can mimic or interfere with the function of hormones in the body

Some studies - exposure to endocrine disruptors

  • May be associated with an increased risk of developing lipoedema.
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Pesticides

  • Commonly used in agriculture and gardening

Studies - exposure to pesticides

  • May be associated with an increased risk of developing lipoedema.
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Heavy metals - lead, mercury

  • Increased risk of developing lipoedema.
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Solvents

Studies - exposure to solvents

  • May be associated with an increased risk of developing lipoedema.
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Formaldehyde

  • Commonly found in building materials, furniture and personal care products

Studies - exposure to formaldehyde

  • May be associated with an increased risk of developing lipoedema.
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Perfluoroalkyl substances (PFAS)

  • Commonly used in non-stick cookware, waterproof clothing, and food packaging.

    Studies - exposure to PFAS may be associated with an increased risk of developing lipoedema.

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Dioxins

  • By-products of industrial processes and waste incineration

Studies - exposure to dioxins

  • May be associated with an increased risk of developing lipoedema.
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Glycol ethers

  • Chemicals that are commonly used as solvents in industrial and commercial applications

Studies - exposure to glycol ethers

  • May be associated with an increased risk of developing lipoedema.
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Arsenic

  • Toxic metalloid that is commonly found in drinking water, food, and air

Studies - exposure to arsenic

  • May be associated with an increased risk of developing lipoedema.
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Cadmium

  • Toxic heavy metal
  • Industrial and agricultural waste a v kávě (!)

  • Studies - exposure to cadmium

  • May be associated with an increased risk of developing lipoedema.
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Lead

  • Toxic heavy metal
  • Commonly found in paint, gasoline, and water

Studies - exposure to lead

-may be associated with an increased risk of developing lipoedema.

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Mercury

  • Toxic heavy metal
  • In fish and other seafood, as well as in dental fillings and certain industrial processes

Studies - exposure to mercury

-may be associated with an increased risk of developing lipoedema.

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Pesticides

  • Used to control pests and weeds

Studies - exposure to pesticides

-may be associated with an increased risk of developing lipoedema.

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Polychlorinated biphenyls (PCBs)

  • Toxic chemicals widely used in the past in industrial and commercial applications

Studies - exposure to PCBs

  • May be associated with an increased risk of developing lipoedema.
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Polycyclic aromatic hydrocarbons (PAHs)

  • Toxic chemicals that are found in air pollution, tobacco smoke and certain food

Studies - exposure to PAHs

  • May be associated with an increased risk of developing lipoedema.
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Volatile organic compounds (VOCs)

  • VOCs are a group of toxic chemicals
  • Commonly found in products such as cleaning supplies, paints, and personal care products

Studies - exposure to VOCs

  • May be associated with an increased risk of developing lipoedema.
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Organochlorine pesticides

  • Group of toxic chemicals commonly used in agriculture and gardening

Studies - exposure to these pesticides

  • May be associated with an increased risk of developing lipoedema.
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Polybrominated diphenyl ethers (PBDEs)

  • Group of toxic chemicals that are commonly used as flame retardants

Studies - exposure to PBDEs

  • May be associated with an increased risk of developing lipoedema.
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Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS)

  • Synthetic chemicals that are widely used in industrial and consumer products

Studies - exposure to these chemicals

  • May be associated with an increased risk of developing lipoedema.
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Dioxins

  • By-products of industrial processes and waste incineration

Studies - exposure to dioxins

  • May be associated with an increased risk of developing lipoedema.
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Nitrosamines

  • Toxic chemicals that are formed when nitrites and amines react together

Studies - exposure to nitrosamines

  • May be associated with an increased risk of developing lipoedema.
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Low-fiber diet

  • May increase the risk of developing lipoedema
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High-fat diet

  • May increase the risk of developing lipoedema
  • Diets that are high in saturated and trans fats
    • May contribute to the development of lipoedema.
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High sugar diet

  • May increase the risk of developing lipoedema
  • Diets that are high in added sugars, in particular, may contribute to the development of lipoedema.
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High-calorie diet

  • May increase the risk of developing lipoedema
  • High in total calories, in particular, may contribute to the development of lipoedema.
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Consuming milk and dairy products

  • May be associated with an increased risk of developing lipoedema
  • Milk and dairy products are high in fat and calories, which may contribute to the development of lipoedema.

Study published in the International Journal of Dermatology

  • Women with lipoedema had significantly higher levels of a protein called beta-casein in their blood
    • Compared to healthy controls
  • Beta-casein is a protein that is found in milk and dairy products.

Another study - women with lipoedema

  • Higher levels of antibodies to casein - found in milk
  • Compared to healthy women
  • Immune response to casein may play a role in the development of lipoedema.
  • More research is needed
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Allergic reaction

  • May play a role in the development of lipoedema

Studies have found that women with lipoedema

  • Have higher levels of antibodies to certain proteins such as
    • Casein, which is found in milk
    • Gluten, which is found in wheat, barley, and rye
  • Suggests that an immune response to these proteins may play a role in the development of lipoedema.
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Dysfunction in the immune system

  • May lead to inflammation and the accumulation of fat in certain areas of the body.
  • More research is needed
  • Not all cases of lipoedema are caused by an allergic reaction
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Multifactorial

  • Lipoedema is a chronic condition with a multifactorial etiology
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Ureaplasma and Mycoplasma

  • Commonly found in the human body, cause various types of infections

Some studies - suggested that Ureaplasma and Mycoplasma infections

  • May be associated with an increased risk of developing lipoedema
  • More research is needed to confirm the link and to understand the underlying mechanisms.

A study published in the Journal of Lipoedema

  • Women with lipoedema had a higher rate of Ureaplasma and Mycoplasma infections
    • Compared to healthy controls
  • Study suggests that Ureaplasma and Mycoplasma infections may play a role in the development of lipoedema.

Another study published in the Journal of Lipoedema

  • Women with lipoedema had higher levels of antibodies to Ureaplasma and Mycoplasma
    • Suggests that an immune response to these bacteria may play a role in the development of lipoedema.
  • More research is needed
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Borreliosis - Lyme disease - Borrelia burgdorferi

Some studies - suggested Borreliosis may be associated with an increased risk of developing lipoedema

- more research is needed

A study published in the Journal of Lipoedema

  • Women with lipoedema had a higher rate of Borreliosis compared to healthy controls
  • Borreliosis may play a role in the development of lipoedema.

Another study published in the Journal of Lipoedema

  • Women with lipoedema had higher levels of antibodies to Borrelia burgdorferi
  • Suggests that an immune response
  • Bacteria may play a role in the development of lipoedema.
  • More research is needed
  • Borrelia may be present in the fat tissue of people with lipoedema.
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Candida

  • Commonly found in the human body, and studies have found that it is present in the fat tissue of people with lipoedema.
  • Present in the fat tissue of people with lipoedema.
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Staphylococcus aureus

  • Commonly found on the skin, and studies have found that it is present in the fat tissue of people with lipoedema.
  • More research is needed
  • Present in the fat tissue of people with lipoedema.
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Streptococcus pyogenes

  • Can cause a variety of infections, including strep throat and skin infections.
  • Present in the fat tissue of people with lipoedema.
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Escherichia coli

  • Commonly found in the human gastrointestinal tract
  • Can cause urinary tract infections and other infections.
  • Present in the fat tissue of people with lipoedema.
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Pseudomonas aeruginosa

  • Can cause a variety of infections, including lung infections and skin infections.
  • Present in the fat tissue of people with lipoedema.
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Proteus mirabilis

  • Can cause urinary tract infections and other infections.
  • Present in the fat tissue of people with lipoedema.
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Klebsiella pneumoniae

  • Can cause lung infections and other infections.
  • Present in the fat tissue of people with lipoedema
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Multiple symmetric lipomatosis (MSL)

  • Hyperlipidemia, hyperuricemia, hypothyroidism, and diabetes mellitus
  • Reported but are not consistent amongst those affected
  • Should be tested for sleep apnea
  • Myxoid liposarcoma was reported in one case
  • Slowly progressive axonal sensory
  • Autonomic peripheral neuropathies have been reported
  • Impairment of autonomic function has been suggested as a cause of sudden death
  • Neuropathology is a distal axonal demyelination
    • Different from that associated with alcohol intake
    • Impairment seems to be prevalently parasympathetic
  • Ten year follow-up, 10% of 31 patients died from sudden death due to autonomic neuropathy
  • Surgical placement of a cardiac pacemaker may be needed
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Multiple symmetric lipomatosis (MSL)

Multiple Symmetric Lipomatosis (Madelung's disease/syndrome; Launois Bensaude syndrome)

  • Symmetrical accumulation of abnormal tumor-like SAT
  • Benign symmetric lipomatosis
  • no blood or urine biomarkers for MSL
  • Gene(s) remains unknown in a majority of cases
  • Increased SAT
  • Discrete non-encapsulated lipomas or as a confluent increase in SAT in a symmetrical distribution on the
    • Neck, the back, the chest, the upper arms, or on the thighs
  • Usually spares the distal limbs
  • Appearance and location of SAT in MSL can vary
  • Three types:

Whole body MSL

MSL-associated lipodystrophy

  • Noted to spare the forearms
  • Entire body can be clearly affected
  • May be easily confused with global obesity or lipedema stage III

MSL Types I and II

  • With associated muscle and normal fat atrophy
  • May be confused with partial lipodystrophy
  • Rare cases, MSL SAT can invade the
    • Lingual muscles of the tongue
    • Vocal cords and compress the recurrent laryngeal nerve causing hoarseness
    • Increase periorbital fat
  • Tracheal or esophageal compression
  • Superior vena cava syndrome can be found in 15%–20% of patients
  • Dorsocervical fat pad (buffalo hump)
    • Can be found both in MSL
    • HIV-associated lipodystrophy

Type II body

  • Shoulder girdle, the upper arms, the thorax, the back, the abdomen and upper buttocks
  • Grew around the testicles in the scrotum
    • Contiguous with MSL tissue in the perineum and the root of the penis
  • Rare is growth of the MSL fat on the hands

Combination of Types II and III

  • MSL fat grows, normal fat and muscle can undergo wasting
    • Can be confused with a partial lipodystrophy

Type III

  • Thigh (female type) - Rarest type
  • Clinically similar to and may be instead, the RAD, lipedema
  • Women tend to have Type II and III MSL with widespread altered SAT

MSL inheritance

  • Through mitochondrial mutations in a few familial cases
    • Multiple deletions of mitochondrial DNA
    • Myoclonus epilepsy
    • Ragged-red fibers (MERRF) tRNA(Lys) A>G(8344) mutation
  • mitochondrial mutations in only 2 of 12 patients studied
  • Chalk et al found no mitochondrial pathology or mutations in four siblings with MSL
    • May require a combined effect of alcohol (or other insult) and a currently unknown genetic mutation.

Histology of MSL fat

  • fat cells have been described as smaller than normal or normal sized
  • Derived from brown adipose tissue (BAT) or as white adipose tissue (WAT) that transdifferentiates into BAT
  • Adipocytes in MSL SAT are monovacuolar or multivacuolar
  • Containing stem and immune cells
  • Cells were
    • Polymorphic
    • With thin microfilaments suggestive of elevated metabolic activity
    • Multivacuolar
    • Large mitochondria packed with cristae suggesting a more BAT phenotype in MSL

MSL SAT may arise

  • From a stem cell population either destined to form BAT, or WAT that transdifferentiates to BAT
  • UCP-1 levels help track BAT features
  • Cells isolated from the MSL SVF did not increase UCP-1 in response to noradrenaline
    • Even though MSL cells express all three beta-AR
  • In MSL cell culture, catecholamines
    • Did not increase lipolysis, expression of inducible nitric oxide synthase (iNOS) or PPARgamma coactivator-1
  • Cytokine and adipokine levels in MSL are also mixed
  • Multilocularity of MSL SAT is suggestive of BAT
  • Increase in MSL fat is extensive and deforming, compressing tissue structures and vessels.
  • Early, MSL SAT is watery but later becomes fibrotic and scars easily
  • Excess fat physically impedes lymph collection and flow
    • protein-rich lymphatic fluid collects in SAT, resulting in lymphedema and tissue hypoxia
  • SAT also grows in the presence of lymphedema
    • Further accumulation of fluid in the setting of decreased oxygen tension leads to fibrosis
  • Ischemia activates the growth of adipose-derived progenitor cells
  • Congestion of lymph nodes by other means, such as lymphoma in the neck
    • Induces fat growth similar to MSL
  • Increased volumes of SAT in MSL, like obesity
    • May therefore be sufficient to externally compress vasculature and lymphatics inducing further growth of SAT as seen in other localized fat collections
  • Impedance of lymph flow into lymph collectors is a local effect

Conditions associated with MSL

Alcohol-induced liver disease

  • Is common in MSL

Hyperlipidemia, hyperuricemia, hypothyroidism, and diabetes mellitus

  • Have been reported
  • Not consistent amongst those affected

Sleep apnea

Myxoid liposarcoma was reported in one case

Slowly progressive axonal sensory and autonomic peripheral neuropathies

  • Have been reported to occur after the development of MSL fat
  • Impairment of autonomic function has been suggested as a cause of sudden death
  • Neuropathology is a distal axonal demyelination
    • Different from that associated with alcohol intake
  • Seems to be prevalently parasympathetic
  • Ten year follow-up
    • Cca 10% of 31 patients died from sudden death due to autonomic neuropathy
  • Surgical placement of a cardiac pacemaker may be needed.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/



Mutation of prospero homeoboxprotein 1

  • Encoded by the PROX1 gene
  • Causes leakage from lymphatics and resultant obesity in heterozygote mice
  • Lymph placed on adipocytes in culture also induces robust growth
  • “lymph makes you fat”
  • PROX1 mutations are not known to be associated with lipedema
  • Microlymphatics may become obliterated in lipedema
    • Leading to backflow and an overall dynamic insufficiency of the lymphatic system
  • Pathophysiology of cellulite development is similar to that in lipedema
  • Leading to the development of joint pains
    • With progression of lipedema, arthritis develops
  • Capillary fragility, ecchymosis, hematomas and venous varicosities are common
  • Kaposi-Stemmer sign is negative in lipedema until the development of lipolymphedema
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Nitrates and Nitrites

  • Commonly used as preservatives
  • Can be found in processed meats, such as bacon, ham, and hot dogs.
  • They have been linked to an increased risk of certain types of cancer
  • May increase the risk of developing lipoedema
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Nonylphenol

  • Found in many cleaning products, pesticides and personal care products
  • Weak estrogenic activity.
Chat GPT


Obesity - lymphedema and aggravati of lipoedema

  • Itself a risk factor for lymphedema
  • Can exacerbate lipedema
  • Lymphedema is the retention of fluid in tissues causing swelling due to congenital or acquired damage to the lymphatic system
  • “lipedema” is defined as “fluid in fat”
    • Excess tissue fluid from lymphedema
      • Adds to the fluid already present in lipedema fat
      • Induces additional fat growth
        • Adding to the burden of fat in lipedema [7]

Microlymphatics may become obliterated

  • In lipedema
  • Leading to backflow and an overall dynamic insufficiency of the lymphatic system
  • Increased tissue pressure and lymphatic vessel leakage
    • Lead to the development of lipolymphedema
  • Lymphedema does not usually develop with cellulite in women
    • Cellulite development is similar to that in lipedema, and LDT
    • Lipedema may therefore be an extreme form of cellulite.
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/


Octylphenol

  • In many personal care products and plastic products
  • Has weak estrogenic activity.
Chat GPT


Parabens

  • Commonly used as preservatives in personal care products
  • Can have weak estrogenic activity.
Chat GPT


Pericytes

  • Play a role in the development and maintenance of blood-vessel integrity
  • Control of immune-cell-trafficking across the vessel walls
  • Increased expression of a pericyte marker indicated the remodeling of the vasculature at the capillary level
    • One of the many factors responsible for the lipedema phenotype
  • Biomedicines 2022, 10, 3081

Perimenopause and menopause

  • Reduced health-related quality of life, as well as higher work impairment. 

Perimenopause

  • A woman’s progesterone levels will begin to decline
    • Ovulation is less regular
  • estrogen is allowed to stimulate tissues
    • Goes through its own peaks and troughs
    • Can trigger hot flashes, night sweats, and mood swings

Menopause



Pesticides

  • Some pesticides have been found to have weak estrogenic activity.
  • Some studies have suggested that the consumption of foods that contain pesticides may be associated with an increased risk of developing lipoedema.
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Platelet Factor 4

  • Novel biomarker-based diagnostic kits
  • Conclusive diagnosis of lipedema at an early stage is challenging
  • Recently identified platelet factor 4 (PF4/CXCL4)
  • Exosomes in mice models and patients with and without known lymphatic pathologies
  • PF4—a plasma-circulating exosomal signature protein—may
    • Employed as a promising novel biomarker in clinical settings to diagnose lymphatic vasculature failure
    • Differentiation of lipedema and lymphedema from obesity
  • Lipedema patients had higher PF4 concentrations in blood-plasma-derived circulating exosomes
    • Some of the underlying characteristics of this disease are a result of lymphatic abnormalities
  • Expression of PF4 was likewise elevated in both young and old PROX-1+/- mice
    • (before and after the onset of obesity)
    • But not in ob/ob mice (nonlymphatic promoted obesity)
  • PF4 might be a new biomarker for lymphatic diseases, including lipedema
  • PF4 is secreted by platelets upon activation during wound healing and inflammation
  • PF4 is a viable biomarker for differentiation between healthy participants and those with lymphatic abnormalities, regardless of obesity
  • PF4 downregulates proteins associated with the tight junction
  • Increases cell permeability
  • PF4 may play a potential role in lymphatic disorders, making the blood vessels more permeable and decreasing lymphangiogenesis
  • Increases T helper 2 (Th2) cytokines
  • Causes the chemotaxis of T cells in a CXCR3-dependent manner
    • T cells (especially Th2 cells) penetrate lymphedematous tissue
      • Contribute to inflammation, fibrosis, and lymphangiogenesis
  • PF4 could help clinicians to identify lipedema
  • Biomedicines 2022, 10, 3081

PDPN - Podoplanin

  • Predominantly expressed by lymphatic endothelium
  • Regulated by PROX-1

Mice lacking podoplanin

  • Displayed reduced lymphatic transport, congenital lymphedema,
  • Cutaneous and intestinal lymphatic channel enlargement
  • Biomedicines 2022, 10, 3081

Polychlorinated biphenyls (PCBs)

  • Industrial chemicals
  • Used in the past
  • Can have weak estrogenic activity.
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Porucha vaziva

  • Weakens nearby structures leading to the development of joint pains
    • With progression of lipedema, arthritis develops
  • Capillary fragility, ecchymosis, hematomas and venous varicosities are common
  • Changes in skin include dryness, fungal infections, cellulitis, and slow wound healing
  • Free fatty acids may be different in both blood and the lipedema SAT
    • //prozánětlivý shift omega 3/6 ???//
  • Dusledek i rizikovy faktor
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/

Overfeeding

  • Eight weeks of overfeeding
    • Increased COL6A3 mRNA expression, VAT mass, and macrophage infiltration
    • Was linked to a more obese phenotype
  • Biomedicines 2022, 10, 3081

PROX-1

  • Master regulator of lymphangiogenesis
  • Microvascular endothelial cells, ectopic expression of PROX-1 upregulated the lymphatic endothelial-cell markers podoplanin and VEGFR-3
  • Biomedicines 2022, 10, 3081

PROX1 mutations

  • Not known to be associated with lipedema in human
  • Mutation of prospero homeoboxprotein 1
    • Encoded by the PROX1 gene
    • Causes leakage from lymphatics
    • Resultant obesity in heterozygote mice
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC4010336/


Chronické prozánětlivé stavy s chronickou aktivací metaloproteináz

  • Soustavný úbytek kolagenu
  • Ztenčení cévních stěn a vznik varixů
  • Kumulace tukových buněk v místě zánětlivé signalizace v tkáních
    • Vznik typických tukových návalků pod poškozenými klouby prozánětlivým stavem
      • Kolena, kotníky, kyčle,...
  • Vyvoláno vším možným dohromady
    • Pochopitelně se více obejvuje, jak stárneme a kumulujeme v sobě kde co
    • Bohužel se objevuje více a více u mladších generací
      • V.s. dílem toxinů z prostředí, špatné stravy a chronických infekcí

Rizikové faktory lipedému

  • ženské pohlaví
  • Gynoidní typ postavy a ukládání tuku do spodní části těla
    • Do volného podkoží na vnitřních stranách nohou,
      • Obzvláště kolem kotníků a v podkoží před kostí holení
  • Celulitida
  • Hormonální terapie
  • Poruchy štítné žlázy (autoimunity)
  • Gynekologické operace
  • Puberta
  • Těhotenství
  • Menopauza
  • Chemoterapie
  • Nadbytek estrogenů, progesteronu
  • Jaterní onemocnění
  • Jiné příčiny hormonální dysbalance
  • Sedavý způsob života
  • Poruchy lymfatického systému dolních končetin a mikrocirkulace
  • Obezita
  • úbytek svaloviny
  • Poruchy pojivové tkáně aj.
  • Složení stravy
  • Hormony - HAT, HRT
  • Pohyb deficitní - zcela zásadní
  • Nesprávná terapie s absencí vytrvalostní pravidelné aktivity


rs1800795

  • Carrier of the mutation increased the risk of developing lipedema by approximately six times
  • Limited number of patients and the lack of ethnic diversity in the cohort (Italian population was considered)
  • Biomedicines 2022, 10, 3081

Genistein

Daidzein

Coumestrol

Zearalenone

Mycotoxins

Bisphenol F (BPF)

Bisphenol S (BPS)

Di-n-octyl phthalate (DNOP)

Di-isodecyl phthalate (DIDP)

Di-n-butyl phthalate (DBP)

Di(2-ethylhexyl) phthalate (DEHP)

Di-n-octyl phthalate (DNOP)

Di-isodecyl phthalate (DIDP)

Octamethylcyclotetrasiloxane (D4)

Decamethylcyclopentasiloxane (D5)

Nonylphenol

4-tertiary-Octylphenol (4-t-OP)

4-nonylphenol

Triclosan

4-Methylbenzylidene camphor (4-MBC)

2,4-Dichlorophenoxyacetic acid (2,4-D)

Atrazine

Propachlor

Linuron

Ethoxyquin

Procymidone

Vinclozolin

Metolachlor

Simazine

Methoxychlor



Artificial sweeteners

  • Some studies have suggested that the consumption of artificial sweeteners may be associated with an increased risk of developing lipoedema
Chat GPT


Tissue Sodium Content Elevated in the Skin and Subcutaneous Adipose Tissue in Women with Lipedema.

  • Participants with lipedema (n?=?10) and control (n?=?11) volunteers matched for biological sex, age, BMI, and calf circumference were scanned with 3.0-T sodium and conventional proton magnetic resonance imaging (MRI)
  • Skin (P?=?0.01) and SAT (P?=?0.04) sodium content
  • Elevated in lipedema
      • Skin: 14.9?±?2.9 mmol/L
      • SAT: 11.9?±?3.1 mmol/L
  • Control participants
      • Skin: 11.9?±?2.0 mmol/L
      • SAT: 9.4?±?1.6 mmol/L
  • Relative fat-to-water volume in the calf
    • Was elevated in lipedema (1.2?±?0.48 ratio)
    • Relative to control participants (0.63?±?0.26 ratio; P?
  • Skin sodium content
    • Was directly correlated with fat-to-water volume (Spearman's rho?=?0.54; P?=?0.01)
  • Providing objective imaging-based biomarkers for differentially diagnosing the under-recognized condition of lipedema from obesity

Sodium

  • Consuming high levels of sodium, commonly found in processed foods
    • Can contribute to weight gain and increase the risk of developing lipoedema.
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Tissue sodium content

  • Significantly elevated in the skin and SAT in lipedema
  • Clearance capacity of lymphatic capillaries is impaired when sodium accumulates in the interstitium
  • Increased sodium levels directly limiting lymphatic clearance
  • Elevated sodium levels may mainly attract salt-sensing macrophages,
    • Release of inflammatory mediators, may play a role in the pathology of lipedema
  • Glycocalyx is composed of proteoglycans, glycoproteins, and associated glycosaminoglycans
    • Line microvessels
    • Act as barriers to prevent the entry of foreign pathogens
  • Microangiopathy seen in lipedema is a result of the impaired glycocalyx barrier function of ECs
    • Due to elevated sodium levels
  • Biomedicines 2022, 10, 3081

Sodium

MRI-based study

  • Lipedema patients had a significantly higher sodium content in the skin and muscle tissue
  • Higher amount of fat in their lower extremities
  • But not their upper extremities, compared to BMI-matched controls
  • MRI may evaluate objective diagnostic criteria to noninvasively differentiate lipedema from obesity
    • Tissue sodium
    • Sodium content of tissues increases with the severity and discomfort of the condition
  • Venous and lymphatic systems must keep the interstitium and capillary bed’s plasma sodium concentrations constant
  • Dysregulated, the accretion of sodium may occur over time
    • Could contribute to the progression of the disease
  • Higher sodium levels in the lower extremities consistent with a gravity dependence
  • Higher tissue sodium content is related to the clinical signs of inflammation and pain
    • And the etiology of the lipedema stages
  • Significant changes in tissue sodium shown in several inflammatory and painful disorders
  • Dysregulation of tissue sodium that may be caused by insufficient vascular clearance or inflammation
    • Central sensitization
    • Joint pain and nociceptive pain
    • Autonomic peripheral neuropathies
  • Biomedicines 2022, 10, 3081

Surgery

  • Following gynecological surgery
  • Surgery of the uterus, ovaries, or fallopian tubes
  • Any surgery with general anesthesia [8]

Syfilis



Syndromic lipedema

Pituitary-specific positive transcription factor 1 (PIT-1), 196C > T

  • Family wherein lipedema, short stature, multiple pituitary hormone deficiencies,
  • Secondary hypothyroidism, and hyperprolactinemia
  • (affected males had short stature and no lipedema)
  • Which produces the amino acid change P24L in exon 1
  • PIT-1 mutation has been linked to many symptoms manifested
    • In pituitary hormonal deficiencies
    • Lipedema
  • PIT-1 - regulatory role in expressing
    • Growth hormone (GH),
    • Prolactin,
    • Thyroid hormone betasubunit genes
  • Biomedicines 2022, 10, 3081

Heavy metals

  • Some studies have suggested that the consumption of foods that contain heavy metals may be associated with an increased risk of developing lipoedema.
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Trans fats

  • Trans fats, which are found in many processed foods, have been linked to weight gain and obesity, which may increase the risk of developing lipoedema.
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Antecedent trauma



Triclosan

  • Commonly used as an antimicrobial agent in personal care products
  • Weak estrogenic activity.
Chat GPT


High-fat diet (HFD) feeding in mice

  • Expressions of laminin 2 (LAM2), laminin 4 (LAM4), and several collagen subunits were upregulated
  • Notably LAM4 was predominantly upregulated in obese SAT samples at both mRNA and protein
  • Biomedicines 2022, 10, 3081

Virové onemocnění / zápal plic


Williams syndrome

  • 1.5 million base pair deletion of chromosomal 7q11.23
  • Resulting in the loss of a series of genes including ELN for elastin
    • Important component of connective tissue
  • Signs and symptoms including a lipedema phenotype
    • In both males and females
  • Aortic stiffness develops in Williams syndrome and in lipedema [7]


Zánět

  • Strong inflammation component [8]

Histologický nález svědčící pro zánět

  • Non-Obese Lipedema adipocyte area
    • Was larger than Non-Obese Controls (p = 0.005)
    • Similar to Obese Lipedema and Obese Controls.
  • Macrophage numbers were
    • Significantly increased in Non-Obese (p < 0.005) and Obese (p < 0.05) Lipedema skin and fat compared to Control groups
  • No differences in
    • T lymphocytes
    • Mast cells comparing Lipedema to Control in both groups
  • Increased dermal vessels in Non-Obese Lipedema patients (p < 0.001)
    • Compared to Non-Obese Controls.
  • Significant increase in lymphatic vessel area
    • But not in number or perimeter in Obese Lipedema participants (p < 0.05) compared to Controls (Obese and Non-Obese)
  • Areas of angiogenesis were found in the fat in 30% of lipedema participants but not controls
  • Hypertrophic adipocytes, increased numbers of macrophages and blood vessels, and dilation of capillaries in thigh tissue of non-obese women with lipedema suggest inflammation
  • Angiogenesis occurs independent of obesity
  • Demonstrates a role of altered vasculature in the manifestation of the disease
  • onlinelibrary.wiley.com/doi/10.1155/2019/8747461

Loss of elastic recoil

  • Allowing more fluid to enter the interstitial space and accumulate
    • Dissemination of fluid in the tissue’s interstitial space and its attachment to glycosaminoglycans

Glycosaminoglycans, proteoglycans

  • Sodium and water are usually bound by glycosaminoglycans because of their potent negative charge
  • Concentration of glycosaminoglycans rises when the amounts of salt or water in the ECM increase
  • Excess fluid promoting proteoglycan production
  • Free and bound to proproteoglycans and glycosaminoglycans, also increases lymphedema in the enlarged ECM

Disturbance to the glycocalyx

  • Lines all vessels and is made up of proteoglycans, glycoproteins
  • Related glycosaminoglycans—may cause microangiopathy in lipedema patients
  • Tissue of lipedema patients has higher sodium concentrations
    • Impair the glycocalyx barrier function of ECs
    • Making them more prone to inflammation

ECM also undergoes pathological remodeling

  • Differentiated spheroids derived from lipedema ADSCs
    • Higher expression levels of basement membrane components of laminin (LAM) and collagen VI (COL6A3)
  • Lower expression of fibronectin (FN)
  • Elevated expression of both LAM and COL6A3 has previously been linked to the obese phenotype
  • Biomedicines 2022, 10, 3081

O úroveň výše

Poslední aktualizace: 6. 10. 2024 21:51:18