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