Hyperlipidemia is common and can manifest as xanthomas, which are skin lesions caused by lipid deposition. The morphology and location of xanthomas can provide clues to the underlying lipid disorder. Hyperlipidemias can be primary/familial due to genetics or secondary due to other conditions. Treatment involves identifying the cause, reducing dietary and caloric intake, medication, and procedures to remove xanthomas.

1. HYPERLIPIDEMI
AS
DR Y SRI HARSHA

2. 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

3. 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

4. CLASSIFICATION OF
LIPOPROTEINS

5. 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

6. LIPOPROTEIN SYNTHESIS
Occurs by 2 major pathways:-
1. EXOGENOUS PATHWAY
2. ENDOGENOUS PATHWAY

8. EXOGENOUS PATHWAY
Dietary 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

10. ENDOGENOUS PATHWAY
Hepatic 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

11.  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.

12. Classification of hyperlipidemias
 Hyperlipidemias can be classified into :
1. Primary/familial hyperlipidemia:- usually due to
genetic causes
2. Secondary hyperlipidemia:- results from another
underlying disorder that leads to alterations in plasma
lipid and lipoprotein metabolism

13. PRIMARY
HYPERLIPIDEMIA
 Are classified further based on class of lipoproteins
which are in excess ( FRIEDRICKSON
CLASSIFICATION)

17. XANTHOMAS
 Definition:- skin lesions which develop as a result of
intracellular and dermal deposition of lipid.
 Various types of xanthomas seen are:-
1. Eruptive xanthomas
2. Tuberous/tuberoeruptive xanthoma
3. Tendinous xanthoma
4. Plane xanthoma
5. Verrucous xanthoma

18. 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

19. PATHOGENESIS

20. 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

21. DIFFERENTIAL DIAGNOSIS
Xanthoma disseminatum Papular xanthoma
Eruptive histiocytosis
Disseminated granuloma annulare

22. 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

23. HISTOPATHOLOGY
• Large aggregates of foamy cells in the dermis, often accompanied by
fibrosis but without a large no of inflammatory cells

24. DIFFERENTIAL DIAGNOSIS
Erythema elevatum diutinum
Multicentric reticulohistiocytosis

25. 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

26. 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

27. Differential Diagnosis
Giant cell tumor of
tendon sheath
Rheumatoid nodule Subcutaneous
granuloma annulare

28. PLANE XANTHOMAS
 Yellow- orange, non inflammatory macules, papules, plaques & patches
which are circumscribed/diffuse
 Sites can give rise to clues for certain underlying diseases

30. 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

31. Differential diagnosis for
xanthalesmas
syringomas
Necrobiotic xanthogranuloma

32. Periocular xanthogranuloma Palpebral sarcoidosis

33. 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

34. 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

35. 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

36. 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 mucosa
2. Generalised lymphadenopathy, hepatosplenomegaly
3. Thrombocytopenia
4. Peripheral neuropathy & corneal opacities
 Diagnosis : low level of HDL cholesterol with near complete absence of
apo A1, total cholesterol levels are low

37. SECONDARY
HYPERLIPIDEMIAS
 Occur secondary or exacerbated by few diseases or medications
1. Diabetes mellitus
2. Lipodystrophies
3. Chronic cholestasis
4. Hepatocellular disease
5. Nephrotic syndrome
6. Chronic renal failure
7. Drugs ( oral retinoids, corticosteroids, cyclosporine )

38. 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

42. 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 TCA
3. Cryosurgery