Hyperlipidemias
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Transcript of Hyperlipidemias
HYPERLIPIDEMIAS
DR Y SRI HARSHA
INTRODUCTION
Hyperlipidemia is quite common in the general population
They manifest cutaneously as XANTHOMAS ( xanthos = yellow (Greek)) which may present with various morphologies
The morphology & anatomic location of these lesions can suggest the type of underlying lipid disorder or the presence of paraproteinemia
Early recognition of these lesions can make a significant impact on the diagnosis, management & prognosis of patients who suffer from an underlying disease
BASICS OF LIPID METABOLISM
Majority of plasma lipids are transported in complex structures known as LIPOPROTEINS.
Structure of a lipoprotein :-1. Hydrophilic outer shell –
consists of phospholipids, free cholesterol, & specialized proteins known as APOPROTEINS ( which differ among various lipoproteins )
2. Hydrophobic core – triglycerides & cholesterol esters
CLASSIFICATION OF LIPOPROTEINS
NORMAL (mg/dl)
BORDERLINE (mg/dl)
HIGH (mg/dl)
Total cholesterol
< 200 200 - 239 > 240
Fasting TGL < 150 150 - 199 200 – 499
HDL < 30 40 – 50 > 60
LDL < 100 130 – 159 160 – 189
LIPOPROTEIN SYNTHESIS
Occurs by 2 major pathways:-
1. EXOGENOUS PATHWAY2. ENDOGENOUS PATHWAY
EXOGENOUS PATHWAYDietary fat intake in the form of TRIGLYCERIDES ( TGL )
Triglycerides are acted upon by pancreatic lipase & converted to free fatty acids (FFA) & monoglycerides
They are absorbed by the intestinal epithelium & later reformed and packed with a small amount of cholesterol esters into a CHYLOMICRON
Chylomicrons enter the lymphatics & eventually into the systemic circulation via the thoracic duct
Hydrolysis of the core triglycerides occurs (about 70%) , releasing free fatty acids to the peripheral tissue ( this is mediated by lipoprotein lipase (LPL)
enzyme which is bound to capillary endothelium ) leaving behind a chylomicron remnant , which contains cholesterol esters
The chylomicron remnant is taken by the liver by specialized apo B-100/E receptors that recognize the apo lipoprotein E3/E4 on the outer shell and
later degraded
ENDOGENOUS PATHWAYHepatic formation of VLDL ( contains central TGL core, apo
lipoproteins E, B100) and releasing it into the systemic circulation
LPL causes hydrolysis of VLDL thereby removing majority of TGL & cholesterol esters
After hydrolysis, the VLDL remnant (IDL) is taken up by the liver by means of apo B100/E receptors & degraded
Some IDL’s escape hepatocyte uptake & are later stripped of their remaining core TGL’s by extracellular hepatic lipases and get
converted to LDL’s ( has a central core of cholesterol esters & apo B 100)
This LDL goes to the peripheral tissues , where the cholesterol esters are converted to free cholesterol
Hepatocytes play the major role of catabolism of LDL’s by uptaking them through apo B100/E receptors
HDL play an important role in removing cholesterol from peripheral tissues
This HDL’s then transfers the cholesterol esters to other lipoproteins such as LDL’s & chylomicron remnants / VLDL’s for transportation back to liver
Hepatic intracellular cholesterol levels have a direct impact on the activity of HMG-CoA reductase, the rate limiting enzyme of cholesterol synthesis & on the expression of the high affinity apo B-100/E receptor.
Classification of hyperlipidemias
Hyperlipidemias can be classified into :1. Primary/familial hyperlipidemia:- usually
due to genetic causes2. Secondary hyperlipidemia:- results from
another underlying disorder that leads to alterations in plasma lipid and lipoprotein metabolism
PRIMARY HYPERLIPIDEMIA
Are classified further based on class of lipoproteins which are in excess ( FRIEDRICKSON CLASSIFICATION)
XANTHOMAS
Definition:- skin lesions which develop as a result of intracellular and dermal deposition of lipid.
Various types of xanthomas seen are:-1. Eruptive xanthomas2. Tuberous/tuberoeruptive xanthoma3. Tendinous xanthoma4. Plane xanthoma5. Verrucous xanthoma
ERUPTIVE XANTHOMAS• Erythematous to yellow papules , 1-5 cm in diameter• Sites:- extensor aspects of extremities, buttocks & hands• Early stages – lesion may have an erythematous halo, with
pain & tenderness• Koebner phenomenon is seen • They can occur in either primary or secondary
hyperlipidemias• Usually seen in familial hyperchylomicronemia,
endogenous familial hypertriglyceridemia & type 5 primary hyperlipidemias
PATHOGENESIS
HISTOPATHOLOGY• Lipid deposits in the form of FOAM CELLS ( lipid laden
macrophages ) seen in the reticular dermis• Early stages :- foam cells are smaller in size & no with a mixed
inflammatory infiltrate consisting of neutrophils & lymphocytes• Late stages :- more typical appearance of a xanthoma is seen but
with fewer foam cells
DIFFERENTIAL DIAGNOSIS
Xanthoma disseminatum Papular xanthoma
Eruptive histiocytosis Disseminated granuloma annulare
TUBEROUS/ TUBEROERUPTIVE XANTHOMAS
• They are clinically & pathologically related & are described often as a continuum
• Tuberoeruptive :- pink-yellow papules/nodules on the extensor surfaces , esp. elbows & knees
• Tuberous :- lesions are larger than tuberoeruptive xanthomas ( size › 3 cm )
• Seen in familial hypercholesterolemia, familial dysbetalipoproteinemias
HISTOPATHOLOGY
• Large aggregates of foamy cells in the dermis, often accompanied by fibrosis but without a large no of inflammatory cells
DIFFERENTIAL DIAGNOSIS
Erythema elevatum diutinum
Multicentric reticulohistiocytosis
TENDINOUS XANTHOMAS
• Firm, smooth, nodular lipid deposits seen over the Achilles tendon, extensor tendons of hands, knees , elbows with normal looking overlying skin
• Characteristically found in familial hypercholesterolemia, familial dysbetalipoproteinemias, hypothyroidism
• They can develop even in absence of a lipoprotein disorder
HISTOPATHOLOGY Similar to tuberous xanthoma, but foam cells are of larger
size
Multiple foam cells were surrounded by macrophages within the collagen fibrous connective tissue of the tendon, suggestive of xanthomas
Differential Diagnosis
Giant cell tumor of tendon sheath Rheumatoid nodule Subcutaneous
granuloma annulare
PLANE XANTHOMAS Yellow- orange, non inflammatory macules, papules, plaques & patches
which are circumscribed/diffuse Sites can give rise to clues for certain underlying diseases
Location of plane xanthoma Underlying disease
Intertriginous areas ( ante cubital fossa, web spaces of fingers)
Homozygous familial hypercholesterolemia
Palmar creases ( XANTHOMA STRIATUM PALMARE )
Dysbetalipoproteinemia
XANTHALESMA/ XANTHALESMA PALPEBRUM ( eyelids )Plane xanthoma of cholestasis ( plaques over hands & feet , but can become generalized )
Biliary atresia, primary biliary cirrhosis due to accumulation of unesterified cholesterol in the blood
Plane xanthomas seen in a normolipiemic person ( neck, upper trunk, flexural folds, periorbital regions )
Underlying monoclonal gammopathy due to plasma cell dyscrasia, B-cell lymphoma, Castleman’s disease, CML
Differential diagnosis for xanthalesmas
syringomas Necrobiotic xanthogranuloma
Periocular xanthogranuloma
Palpebral sarcoidosis
VERRUCIFORM XANTHOMAS Asymptomatic, planar/ verrucous solitary plaques around 1-2 cm in diameter Occur primarily in mouth, anogenital/ periorificial sites No associated hyperlipidemia is seen Also can be seen in lymphedema, epidermolysis bullosa, pemphigus, DLE,
GVHD, CHILD syndrome
Cerebrotendinous xanthomatosis
Autosomal recessive Results from a defect in sterol 27 hydroxylase enzyme
with consequent increased production of cholestanol & 7 – hydroxy cholesterol which accumulate throughout the body
CNS accumulation causes myelin destruction leading to mental retardation, seizures, spasticity, ataxia
Patient may present during childhood / early adult life Other features are early onset cataracts, diarrhea,
premature osteoporosis Treatment is by chenodeoxycholate
Sitosterolemia Autosomal recessive Results from mutations in the gene ABCG5/ABCG8 which
encodes the proteins sterolin -1 & 2 in the enterocytes & hepatocytes
These proteins act together to form a lipid transporter that is thought to facilitate immediate excretion of any plant sterols absorbed ( beta – sitosterol, sitostanol, campesterol )
Patients suffer from impaired growth, anemia, thrombocytopenia, arthritis & are at a risk of premature CVD
Diagnosis is made based on the serum plant sterol levels Treatment is by EZETIMIBE
TANGIER DISEASE Cholesterol esters accumulate in foam cells throughout the
reticulo endothelial system Results from mutations in gene encoding for ABCA1 Clinically,1. Enlarged yellow orange tonsils with similar deposits in rectal
mucosa2. Generalised lymphadenopathy, hepatosplenomegaly3. Thrombocytopenia4. Peripheral neuropathy & corneal opacities Diagnosis : low level of HDL cholesterol with near complete
absence of apo A1, total cholesterol levels are low
SECONDARY HYPERLIPIDEMIAS
Occur secondary or exacerbated by few diseases or medications
1. Diabetes mellitus2. Lipodystrophies3. Chronic cholestasis4. Hepatocellular disease5. Nephrotic syndrome 6. Chronic renal failure7. Drugs ( oral retinoids, corticosteroids, cyclosporine )
MANAGEMENT Identification of the underlying lipoprotein disorder
& other possible exacerbating factors Reduce intake of dietary fat ( less than 30% of total
caloric intake) Mono unsaturated fats such as olive oil & omega -3
unsaturated fatty acids should comprise majority of the fat intake
Have to reduce total caloric intake & achieve ideal body weight
Alcohol avoidance & smoking cessation is essential Various lipid lowering agents can be used in
addition to dietary measures
Treatment of xanthalesmas
Surgical excision followed by suture or second intention healing
Destructive methods:1. Lasers (CO2, pulsed-dye, erbium-YAG lasers)2. Chemical agents like TCA3. Cryosurgery