[考生加油]Dermatological Recall: Chapter 135. Xanthomatoses and Lipoprotein Disorders

Fitzpatrick's Dermatology in General Medicine

Chapter 135. Xanthomatoses and Lipoprotein Disorders

如果要儘快掌握本章重點，不妨看一下筆者仿照Surgical Recall寫的Dermatological Recall。

• 建議可以先遮住右邊，想一下答案大概是什麼。
• (5)表示答案有五項。(訣)表示有筆者自編的口訣。

鄭煜彬

Xanthomatoses and Lipoprotein Disorders: introduction
Xanthoma內有哪種細胞?	Chlesterol & triglycerides in foamy macrophages
Xanthoma會在哪些組織?(3)	Skin, tendons, tonsillar(Tangier dz)
Xahthoma形成有哪些mechanisms (3)	Local factors( heat, movement, and friction)→↑LDL capillary leakage→↑ V-CAM & E-selectin引來Mφ Mφs’ scavenger receptors ↑ LDL uptake MφIn situ lipid synthesis
Xanthomas型態分為哪四大類?	Eruptive, tubo-eruptive or tuberous, tendinous, or planar.
Xanthomas的病理學特徵為何?	Foam cells: Mφcontain lipid. Eruptive: foam cells+ lymphoid cells, histiocytes, neutrophils, and free lipid in the dermis. Tuberous/ Tendonous: foam cells+ cholesterol clefts(doubly refractile) Xanthelasmata: superficial location/eyelids(striated muscle, vellus hair, and/or a thinned epidermis).
Lipid and Lipoprotein Metabolism
Cholesterol合成的速率決定步驟是哪個酵素?	HMG-CoA reductase
Cholesterol吸收和合成的比例大概多少?	1:4
哪些食物富含Cholesterol?	Eggs, butter, whole milk, and animal fats as found in meat
植物的Cholesterol叫做?	Plant sterols (β-sitosterol and campesterol)
Cholesterol可做成那些產物?(5)	Bile acids—cholic acid & chenodeoxycholic acid Steroid hormones: estrogen, testosterone, & cortisol
Cholesterol不能合成Bile acids會產生什麼疾病?	cerebrotendinous xanthomatosis(CTX)
五種lipoprotein代謝的流程為何?	小腸→Chylomicrons→血管→chylomicron remnant→肝→VLDL→血管→VLDL remnant(IDL) →肝→LDL→肝/adipocyte Mn: C Cr V Vr L(語法：去過血管變~remnant，去過肝變~LDL)
五種lipoprotein代謝過程中，哪種成分逐漸降低?	triglycerides
小腸會製造哪兩種lipoprotein?	Chylomicrons & HDL
哪些lipid會被ABCG5/8送回腸道?	Cholesterol,β-sitosterol and campesterol
承上，ABCG5/8異常會造成哪種疾病?	Phytosterolemia(β-sitosterol)，會造成tendinous xanthomas.
Chylomicrons有哪四種lipoproteins?哪種會和血管的lipoprotein lipase(LPL)作用?	A, B48, CII, E。CII
Chylomicrons remnant有哪兩種lipoproteins?哪種會和肝的Chylomicrons remnant receptor作用?	B48, E。E
VLDL有哪三種lipoproteins? 哪種會和血管的LPL作用?	B100, CII, E。CII
VLDL remnant(IDL) 有哪兩種lipoproteins?哪種會和肝的LDL receptor作用?	B100, E。B100
LDL有哪種lipoprotein能與肝的LDL receptor作用?	B100
HDL有哪兩種lipoprotein能將cholesterol回收入肝?	apoA-I & apoA-II
無法代謝chylomicrons and VLDL會造成哪種xanthoma?	Eruptive(severe hypertriglyceridemia)
無法代謝chylomicron and VLDL remnant會造成哪種xanthoma?	tubo-eruptive xanthomas (combined hyperlipidemia)
HDL deficiency(apoA-I不足) 會造成哪種xanthoma?	tubo-eruptive xanthomas
無法代謝LDL會造成哪種xanthoma?	tendinous xanthomas(familial hypercholesterolemia)
Cholestanol or plant sterols過多會造成哪種xanthoma?	tendinous xanthomas
哪些familial lipoprotein disorders容易產生premature CHD?	Familial hypercholesterolemia(IIa) Familial Lipoprotein (a) Excess(tendinous or tubo-eruptive) Familial Combined Hyperlipidemia(tendinous or tubo-eruptive)IIb Familial Dyslipidemia(tubo-eruptive)III Familial Hypoalphalipoproteinemia(tubo-eruptive)IV Tangier Disease(yellow/orange hyperplastic tonsils)
承上，這些疾病是否容易產生xanthoma?	大多不會
哪些familial lipoprotein disorders容易產生xanthoma?	Familial Hypercholesterolemia(tendinous)IIa Phytosterolemia(tendinous) Cerebrotendinous Xanthomatosis(tendinous) Dysbetalipoproteinemia(tubo-eruptive)III Marked HDL Deficiency(tubo-eruptive)
Tendinous xanthomas好發於何處tendon?	Subcutaneous nodules in fascia, ligaments, extensor tendons of hands, knees, elbows, and Achilles tendons
Tenidnous xanthomas是因為血中哪些成分高?	Sterols: cholesterol,
Tendinous xanthomas與那些疾病有關?	Familial hypercholesterolemia (FH, LDL>300mg/dL), phytosterolemia (plant sterols: β-sitosterol and campesterol), or cerebrotendinous xanthomatosis (cholestanol).
Tendinous xanthomas有哪些治療?	Statins, ezetimibe, anion exchange resins, LDL apheresis
Familial Hypercholesterolemia(IIa)有哪三種類型?	Homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, or defective apoliprotein-B100
Familial Hypercholesterolemia造成哪種xanthoma?	Tendinous or tuberous xanthomas.
Familial Hypercholesterolemia的臨床特徵為何?	Arcus senilis, tendinous xanthomas, xanthelasma LDL↑, normal TG & HDL.
Homozygous familial hypercholesterolemia另有哪些臨床特徵?	Tubo-eruptive xanthomatous plaques (over the extremities, buttocks, and hands), Intertriginous xanthomas(極具指標性), CHD/aortic stenosis <20y/o, LDL>600mg/dL(heterozygous>300 mg/dL)
Familial Hypercholesterolemia造成的CHD要如何預防?	服用Statins+ ezetimibe，使LDL <130 mg/dL 有必要時LDL apheresis
Phytosterolemia血中那些成分會高?	Elevated LDL cholesterol, plasma β-sitosterol & campesterol
Phytosterolemia的臨床症狀為何?	tendinous and tuberous xanthomas and premature CHD
Phytosterolemia有哪些治療?	Ezetimibe
CTX血中那種成分會高?	Cholestanol
CTX的臨床症狀為何?	Cerebellar ataxia and dementia, tendinous xanthoma
CTX患者為何無法用cholesterol製造bile acid?	Defects in the sterol 27-hydoxylase gene
CTX有哪些治療?	Oral chenodeoxycholate 250 mg TID
Tubo-eruptive, planar, and palmar xanthomas與那些疾病有關?	Combined hyperlipidemia(Cholesterol+ TG) & marked HDL deficiency, monoclonal gammopathies, multiple myeloma
Tubo-eruptive, planar, and palmar xanthomas是因為血中哪些成分高?	Cholesterol+TG= intestinal and liver remnant lipoprotein particles (dysbetalipoproteinemia)
Tubo-eruptive, planar, and palmar xanthomas有哪些治療方式?	Dietary modification, statins, fibrates, and niacin
Dysbetalipoproteinemia(IIb & III)血中那些成分會高?	Chylomicron remnants & VLDL remnants(IDL).
Dysbetalipoproteinemia是哪種lipoprotein缺乏/功能不足?	ApoE deficiency，或apoE2/2(正常為3/3)，hepatic lipase deficiency
用哪種檢體測量hepatic lipase活性?	Postheparin plasma (10 minutes after the injection of 100 units/kg body weight of heparin).
Dysbetalipoproteinemia的臨床症狀為何?	Adult with xanthoma striatum palmare(characteristic) , Tubo-eruptive xanthomas on their elbows, hands, and even ears Premature CHD, gout, and diabetes
Dysbetalipoproteinemia的lab為何?	↑non HDL cholesterol (total cholesterol—HDL cholesterol>200 mg/dL) and ↑remnant lipoprotein cholesterol (>100 mg/dL) HDL正常，LDL降低
Dysbetalipoproteinemia有哪些治療?	fibrates, nicotinic acid, or statin
marked HDL deficiency 的LDL與TG如何?	都正常
marked HDL deficiency是哪種lipoprotein缺乏?	apoA-I
marked HDL deficiency的臨床症狀為何?	Corneal opacification, premature CHD in their 30s. tubo-eruptive xanthomas, palmar and planar xanthomas
marked HDL deficiency 的lab為何?	HDL cholesterol <10 mg/dL
marked HDL deficiency有哪些治療?	optimizing all CHD risk factors (LDL <70 mg/dL, TG <150 mg/dL, no smoking, BP <130 mmHg, and HbA1c <7.0%),
Xanthomas還與哪些systemic diseases有關?(4)	monoclonal gammopathies, multiple myeloma, lymphoma and various forms of leukemia
承上，這類xanthoma形成的機轉為何?	Igs bind lipoprotein，延遲chylomicron remnants or VLDL remnants之清除(兩者會高)。
承上，這類xanthoma多半為哪些類型?	Tubo-eruptive, planar, and palmar xanthomas(同combined hyperlipidemia or dysbetalipoproteinemia)
承上，這類xanthoma如何治療?	治療underlying disorder, fenofibrate
Xanthomas還與哪類結構性疾病有關	Prolonged obstruction of the biliary tree (primary biliary cirrhosis and secondary biliary obstruction.)
承上，這類xanthoma的lab為何?	↑ unesterified cholesterol.
承上，這類xanthoma多半為哪些類型?	Plane xanthomas (plaques on hands, feet, and trunk), xanthelasma, and tuberous xanthomas. Jaundice, pruritus, and hyperpigmentation of the skin
承上，這類xanthoma如何治療?	解決obstruction. liver transplantation for stage 4 disease.
Planar xanthoma的臨床特徵為?	Yellow macules, soft papules, or plaques on the upper eyelids (xanthelasma palpebrarum), the wrists and palms (xanthoma striatum palmare), and in intertriginous area.
Xanthelasma好發於何處? 與那些疾病有關?	Eyelids, elevated LDL cholesterol 或完全健康的人
Xanthelasm有哪些治療方式?	Ablative laser therapy(最佳), surgical excision, , trichloroacetic acid, cryotherapy
Eruptive xanthomas有哪些臨床特徵?	Multiple, reddish-yellow papules at extensor surface of extremities & buttocks(Appear suddenly)
Eruptive xanthomas血中哪種成分會高?	Chylomicron and TG (fasting level >1,000 mg/dL, chylomicrons+), 嚴重會pancreatitis
哪些疾病會造成eruptive xanthomas?	Severe Hypertriglyceridemia(typeI: Familial chylomicronemia; typeV: Mixed hyperlipidemia), obesity, alcohol abuse, diabetes (type 2), and drugs
遺傳性Severe Hypertriglyceridemia是哪種酵素/lipoprotein缺乏?	Lipoprotein lipase deficiency or apoC2 deficiency
Severe Hypertriglyceridemia的臨床症狀為何?	Eruptivee xanthoma, Lipemia retinalis (milky plasma which can be visualized in retinal veins) 很少coronary atherosclerosis.
Severe Hypertriglyceridemia的lab為何?	LDL <50 mg/dL ↑chylomicrons and VLDL，導致lipoprotein lipase活性很低
Severe Hypertriglyceridemia有哪些治療?	dietary modification.
哪些藥物會造成eruptive xanthomas	Retinoids, estrogen, and protease inhibitors.
Eruptive xanthomas有哪些治療方式?	限 fat and sugars, weight loss,control diabetes, fibrates & fish oil.
Xanthomas in Children
哪些原因會導致小孩出現xanthomas? (4)	homozygous FH, phytosterolemia/sitosterolemia, CTX, and Alagille syndrome
Alagille syndrome原因為何?	an inherited syndrome of biliary hypoplasia
Alagille syndrome有哪些臨床特徵?	A characteristic facies (a prominent forehead, hypertelorism, pointed chin, and nasal dystrophy), Cirrhosis,
Alagille syndrom是哪種血脂增加?	cholesterol
Alagille syndrom如何治療?	liver transplantation
Verruciform Xanthoma(VX)
VX好發於何處?	oral cavity
VX的病理特徵為?	foamy histiocytes within elongated dermal papillae
Nonmucosal VX要小心何種疾病?	congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD)
還有哪種遺傳疾病會長VX?	Epidermolysis bullosa
Laboratory of xanthomas
完整的lab須包含哪些項目?	urine protein, serum creatinine(排除nephrotic syn.) and a hepatic panel(排除肝炎TG↑ & 膽道阻塞: LDL&Alp↑), fasting glucose(排除DM), thyroid function tests(排除hypothyroidism), a fasting lipid profile, lipoprotein(a), apoE genotyping, β-sitosterol, campesterol, and cholestanol.
Lipid profile抽血須注意何事?	fasts overnight
如何辨別β-sitosterol , campesterol, cholestanol?	gas chromatography
血脂異常的標準為何?	LDL cholesterol (>160 mg/dL) or triglycerides (>150 mg/dL), or decreased levels of HDL cholesterol (<40 mg/dL)
Diabetes, renal disorders(nephrotic syndrome), anabolic steroid使用的lab特色為?	↑TG, ↓HDL
Hypothyroidism and obstructive liver disease的lab特色為?	↑LDL
estrogens and alcohol intake的lab特色為?	↑TG, ↑HDL
Hyperlipidemias的治療
Lifestyle Therapy如何進行?	↑ physical activity /weight control( preventing diabetes, ↓triglycerides, and ↑HDL) Dietary management: ↓saturated fat/trans fats, ↓ cholesterol to <200 mg/day, vegetable oils, fish intake.
↓LDL & TG, ↑HDL有哪些藥物選擇?	↓LDL: Statins > ezetimibe>resins. ↓TG: Fibrates(fenofibrate)> fish oil>niacin therapy. ↑HDL: Niacin
Statin的主要機轉為?	inhibit HMG-CoA reductase
Statin的主要副作用為?	dyspepsia, headaches, muscle or joint aches, liver transaminitis,severe myopathy leading to rhabdomyolysis.
Fibrate有哪兩個藥?	gemfibrozil and fenofibrate((不像gemfibrozil和statin交互作用
Fibrates的主要機轉為?	PPAR-αagonists
Fibrates的主要副作用為?	dyspepsia, gallstones(cholesterol secretion into bile) 會增強warfarin and certain hypoglycemic作用
Niacin以哪種藥最常用?	Niaspan: extended release product (less flushing 2 g/day taken at bedtime)
Niacin的主要副作用為?	flushing(先服aspirin), gastric irritation, and ↑ uric acid, glucose, and liver enzymes
哪兩種病人不宜用niacin?	liver disease, gastric ulcer.
Ezetimibe的主要機轉為?	NPC1L1 inhibitor Cholesterol and plant sterols經由 Niemann-Pick C-like protein 1 (NPC1L1) transporter吸收入腸
哪種人適合用Ezetimibe?	對statins無效者
Ezetimibe和statin並用有何特效?	↓LDL&CRP
有哪些Anion Exchange Resins可降血脂?	cholestyramine, colestipol, and colesevelam
Anion Exchange Resins機轉為何?	bind bile acids in intestine→↑conversion of liver cholesterol to bile acids/↑LDL receptors in liver→↓LDL
Anion Exchange Resins有哪些副作用?	bloating and constipation, ↑TG,阻礙digoxin, tetracycline, d-thyroxine, phenylbutazone, and coumadin吸收
Fish Oil Capsules的機轉為何?	eicosapentanoic acid (EPA) :消炎↓ immune response(↓IL-1, 6 and TNF-α), ↓ helper T cells & delayed hypersensitivity response decohexanoic acid (DHA): 降血脂↓ TG, ↑HDL
Fish oil還可減少哪些疾病?	↓dementia and Alzheimer disease ↓CHD, death from MI

此外，這幾個表也請注意一下。

Table 135-1 Clinical Presentations of Xanthomas

Type of Xanthoma	Genetic Disorders	Secondary Disorders
Eruptive	Familial lipoprotein lipase deficiency	Obesity
	ApoC-II deficiency	Cholestasis
	ApoA-I and apoA-I/C-III deficiency	Diabetes
	Familial hypertriglyceridemia	Medications: retinoids, estrogen therapy, protease inhibitors
	Familial hypertriglyceridemia with chylomicronemia
Tuberous	Familial hypercholesterolemia	Monoclonal gammopathies
	Familial dysbetalipoproteinemia	Multiple myeloma
	Phytosterolemia	Leukemia
Tendinous	Familial hypercholesterolemia
	Familial defective apoB
	Familial dysbetalipoproteinemia
	Phytosterolemia
	Cerebrotendinous xanthomatosis
Planar
Palmar	Familial dysbetalipoproteinemia
	Homozygous apoA-I deficiency
Intertriginous	Familial homozygous hypercholesterolemia	Cholestasis
Diffuse		Monoclonal gammopathies, cholestasis
	Familial hypercholesterolemia
Xanthelasma	Familial dysbetalipoproteinemia	Monoclonal gammopathies
Other
Corneal arcus	Familial hypercholesterolemia
Tonsillar	Tangier disease

Table 135-2 Frederickson Classification of Familial Hyperlipidemias (Only Occasionally Used)

Frederickson Classification	Condition	Defect	Lipoprotein Increase	Type of Xanthoma
Type I	Familial chylomicronemia	Decreased lipoprotein lipase or altered apoC-II	Chylomicrons (and VLDL)	Eruptive xanthomata
Type IIa	Familial hypercholesterolemia Heterozygous    Homozygous	LDL receptor or apoB deficiency	LDL	Tendon, tuberous, plane xanthomas (xanthelasma and intertriginous) 15% with xanthoma by second decade Xanthomata by age 6 years
Type IIba	Familial combined hypercholesterolemia	Decreased LDL receptor and increased apoB	LDL and VLDL	Usually absent, but can have xanthomas as in type IIa
Type III	Familial dysbetalipoproteinemia	Defective apoE-2 synthesis	IDL	Palmar, tuberous, tubo-eruptive xanthoma, xanthelasma
Type IVb	Familial hypertriglyceridemia (pure)	Increased VLDL production and decreased elimination	VLDL	Rare eruptive xanthomas
Type V	Mixed hyperlipidemia	Increased VLDL production and decreased LPL	VLDL and chylomicrons	Eruptive xanthomas

Most familial hyperlipidemias associated with xanthomas are rare.

Box 135-1 Differential Diagnosis of Xanthomas

Eruptive xanthomas Sarcoid Interstitial granuloma annulare Xanthoma disseminatum Juvenile xanthogranulomas Tuberous or tendinous xanthomas Cyst Lipoma Neurofibroma Plane xanthomas Pseudoxanthoma elasticum Amyloidosis Sarcoidosis Xanthelasma Syringoma Sebaceous hyperplasia Adnexal neoplasms