18-Cromwell Cases NLA with Summary Baltimore Onsite 9-21-13 · CAPD HIV (HAART) Glucocorticoids...

Diagnostic DilemmasCase Based Interactive Session

Diagnostic DilemmasCase Based Interactive Session

William Cromwell, MD, FAHA, FNLA

Diplomate, American Board of Clinical Lipidology

Chief Medical OfficerLipoScience, Inc.

ChiefLipoprotein and Metabolic Disorders Institute

Adjunct Associate ProfessorWake Forest University School of Medicine

William Cromwell, MD, FAHA, FNLA

Diplomate, American Board of Clinical Lipidology

Chief Medical OfficerLipoScience, Inc.

ChiefLipoprotein and Metabolic Disorders Institute

Adjunct Associate ProfessorWake Forest University School of Medicine

William Cromwell, MD, FAHA, FNLADisclosures

William Cromwell, MD, FAHA, FNLADisclosures

54 year-old male presents for evaluated of hypertriglyceridemia. o Triglyceride in 1987 was 500 mg/dL.

o Multiple fasting lipid profiles since that time show:Total Cholesterol 280 – 350 mg/dLTriglycerides 400 – 460 mg/dLHDL Cholesterol 35 – 42 mg/dL

o Prior medical therapy includes:Atorvastatin 40 mg daily and Fish oil 2000 mg daily

(DHA+EPA content unknown)o No current lipid lowering medications.

o Diet is a described as “low carbohydrate” diet.

o No routine physical activity

Case RYCase RY

He was evaluated for an episode of chest pain in May 2007 with cardiac enzymes and stress echocardiogram which were unremarkable. Chest pain was felt to be due to gastroesophagealreflux. He is able to engage in activities of choice without complaints.

Past Medical History: Elevated BP (no diagnosis of HTN)

GERDCurrent Medications: None

Family History: Unremarkable Review of Systems: Unremarkable,

Weight unchanged x 6 months

Case RYCase RY

PE: BP 138/86 Pulse 74 Wt 212 lb Ht 68” Waist 38” BMI 32.2Otherwise unremarkable

Case RYCase RY

Baseline

Total-C 300 mg/dL TG 390 mg/dLHDL-C 42 mg/dL LDL-C 178 mg/dLNon HDL-C 258 mg/dL

TSH, LFT, Creatinine all WNLFBS 105 mg/dL

“Low Carb” DietNo Exercise Regimen

What Lipoprotein AbnormalityIs Present?

Is increased lipoprotein related CHD risk present?

What lipid / lipoprotein targets are appropriate?

■ Normal■ Hypoalpha-

lipoproteinemia

■ Complete (FHC)or partial LPLdeficiencyassociated witha secondaryfactor

■ Complete LPLdeficiency

(FHC)■ Primary apoC-II

deficiency

■ Familial dysbeta-lipoproteinemia(type III)

■ Hepatic lipasedeficiency

■ (Primary causeassociated witha secondaryfactor)

Apo B > 75 mg/dL

Apo B < 75 mg/dL

TC:Apo B> 2.4

TC:Apo B < 2.4

■ FamilialhyperTG

■ Partial LPLdeficiency

■ FH■ Polygenic■ FDB■ PCSK9deficiency■ ARH deficiency■ CYP7A1deficiency■ Hypoalphalipo-proteinemia

■ FCH■ β-Sitosterolemia

Normal Chylo + VLDL Chylo Chylo + VLDL Remnants

VLDL LDL VLDL + LDL

NormoTG< 133 mg/dL

TG:Apo B > 8.8

NormoApo B< 120 mg/dL

TG:Apo B < 8.8

HyperTG> 133 mg/dL

NomoTG> 133 mg/dL

HyperApo B> 120 mg/dL

Hyper TG> 133 mg/dL

PrimaryCauses

Algorithm for Differential Diagnosis of HypertriglyceridemiaAlgorithm for Differential Diagnosis of Hypertriglyceridemia

Abbreviations: apo, apolipoprotein; ARH, autosomal recessive hypercholesterolemia; CAPD, continuous ambulatory peritoneal dialysis; Chylo, chylomicrons; CP7A1, cytochrome P450 7A1; DM2, diabetes mellitus type 2; dysbeta; dysbetalipoproteinemia; FCH, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHC, familial hyperchylomicronemia; HAART, highly active antiretroviral therapy; LPL, lipoprotein lipase; PCOS, polycystic ovary syndrome; SLE, systemic lupus erythematosus; TC, total cholesterol; TG, triglyceride.

de Graaf J et al. Nat Clin Pract Endocrinol Metab 2008;4:608-18.

Lipoproteins

Apo B > 75 mg/dL

Apo B < 75 mg/dL

TC:Apo B > 2.4

TC:Apo B < 2.4


VLDL LDL VLDL + LDL

NormoTG< 133 mg/dL

TG:Apo B > 8.8


TG:Apo B< 8.8

HyperTG> 133 mg/dL

NomoTG> 133 mg/dL


Hyper TG> 133 mg/dL

SecondaryCauses

■ Normal ■ DM2■ Metabolic

syndrome■ Abdominal

obesity■ Alcohol■ Glucocorticoids■ Estrogens■ Chronic renal

failure■ Pregnancy

■ SLE withacquired apoC-IIdeficiency

■ DM2■ Metabolic


obesity■ Alcohol■ Hyperthyroidism■ Glucocorticoids■ Chronic renal

failure



obesity■ Alcohol■ Glucocorticoids■ Estrogens■ Chronic renal

failure■ Hemodialysis

■ Nephroticsyndrome

■ Hypothyroidism■ Anabolic

steroids



obesity■ Nephrotic

syndrome■ Cholestasis■ SLE, PCOS,

CAPD■ HIV (HAART)■ Glucocorticoids■ Antipsychotic

drugs■ Pregnancy 3rd

trimester

Abbreviations: apo, apolipoprotein; ARH, autosomal recessive hypercholesterolemia; CAPD, continuous ambulatory peritoneal dialysis; Chylo, chylomicrons; CP7A1, cytochrome P450 7A1; DM2, diabetes mellitus type 2; dysbeta; dysbetalipoproteinemia; FCH, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHC, familial hyperchylomicronemia; HAART, highly active antiretroviral therapy; LPL, lipoprotein lipase; PCOS, polycystic ovary syndrome; SLE, systemic lupus erythematosus; TC, total cholesterol; TG, triglyceride.

de Graaf J et al. Nat Clin Pract Endocrinol Metab 2008;4:608-18.

Lipoproteins

Algorithm for Differential Diagnosis of HypertriglyceridemiaAlgorithm for Differential Diagnosis of Hypertriglyceridemia

Apo B > 75 mg/dL

Apo B < 75 mg/dL

TC:Apo B > 2.4

TC:Apo B < 2.4


VLDL LDL VLDL + LDL

NormoTG< 133 mg/dL

TG:Apo B > 8.8


TG:Apo B < 8.8

HyperTG> 133 mg/dL

NomoTG> 133 mg/dL


Hyper TG> 133 mg/dL

Apo B = 81 mg/dL ■ Familial dysbeta-lipoproteinemia(type III)

■ Hepatic lipasedeficiency

■ (Primary causeassociated witha secondaryfactor)

PrimaryCauses

SecondaryCauses



obesity■ Alcohol■ Hyperthyroidism■ Glucocorticoids■ Chronic renal

failure

TC = 300 mg/dL TC:Apo B = 3.7

TG = 390 mg/dLTG:Apo B = 4.93

Apo E phenotype = E2/E2

Case RYCase RYWhat Lipoprotein Abnormality Is Present?What Lipoprotein Abnormality Is Present?

2 Major Risk Factors (age, low HDL-C)10-year Framingham Risk Score = 12% (moderately high risk)

What additional evaluation should be considered?

A. hs-CRP test?B. Non-Invasive Imaging?

(Coronary Calcium Score, CIMT)C. Other testing?

Case RYCase RYWhat Is The Patients Cardiovascular Risk?What Is The Patients Cardiovascular Risk?

2 Major Risk Factors (age, low HDL-C)10-year Framingham Risk Score = 12% (moderately high risk)

Additional Results:

hs-CRP = 4.710-year Reynolds Risk Score = 10% (moderately high risk)

Coronary Calcium Score = 1310 (>95th percentile)10-year MESA Risk Score = 30% (CHD Risk Equivalent)Lp(a) = 15

Overall CHD Risk = Very High Risk

Case RYCase RYWhat Is The Patients Cardiovascular Risk?What Is The Patients Cardiovascular Risk?


Goals: Baseline:

LDL-C: < 70 mg/dL 178 mg/dLnon HDL-C: < 100 mg/dL 258 mg/dLTG: < 150 mg/dL 390 mg/dLOptionalApo B: < 70 mg/dL 81 mg/dL

Case RYCase RYWhat Are The Appropriate Targets of Therapy?What Are The Appropriate Targets of Therapy?

Clinical Intervention

Therapeutic Lifestyle ChangesWeight Optimization Mediterranean Eating Pattern

25% calories from fat, low refined carbohydrates

Exercise 45 minutes, 5 days per week

Pharmacologic Therapy

Atorvastatin 40mg dailyFenofibrate 160 mg daily

Case RYCase RYWhat Management Options Should Be Considered?What Management Options Should Be Considered?


Goals: Baseline: 6 months(24 lb loss)

LDL-C: < 70 mg/dL 178 mg/dL 73 mg/dLnon HDL-C: < 100 mg/dL 258 mg/dL 104 mg/dLTG: < 150 mg/dL 390 mg/dL 142 mg/dLOptional Apo B: < 70 mg/dL 81 mg/dL 55 mg/dL

Case RYCase RYResponse To TherapyResponse To Therapy

Therapy

Baseline 6 Month

Atorvastatin40 mg

Fenofibrate 160 mg

TLC (24# Wt Loss)

Total-C (mg/dL) 300 146

TG (mg/dL) 390 142HDL-C (mg/dL) 42 45

LDL-C (mg/dL) [Goal < 70 mg/dL] 178 73

% Change vs. Baseline 58%

Non HDL-C[Goal < 100 mg/dL] 258 104

Apo B (mg/dL)[Goal < 70 mg/dL] 81 55


Summary Case RYSummary Case RY

Case RYCase RYWhat Management Options Should Be Considered?What Management Options Should Be Considered?


Therapeutic Lifestyle ChangesWeight Optimization Mediterranean Eating Pattern

25% calories from fat, low refined carbohydrates

Exercise 45 minutes, 5 days per week

Pharmacologic Therapy Adjustment?

Therapy

Baseline 6 Month

Atorvastatin40 mg

Fenofibrate 160 mg

TLC (24# Wt Loss)

1 Year

Atorvastatin40 mg

TLC (57# Wt Loss)

Total-C (mg/dL) 300 146 142

TG (mg/dL) 390 142 54HDL-C (mg/dL) 42 45 75

LDL-C (mg/dL) [Goal < 70 mg/dL] 178 73 64

% Change vs. Baseline 35% 64%

Non HDL-C[Goal < 100 mg/dL] 258 104 67

Apo B (mg/dL)[Goal < 70 mg/dL] 81 55 40


Summary Case RYSummary Case RY

17 year-old male presents for evaluated of hyperlipidemia.

Patient first became aware of abnormal serum lipids at approximately age 8 when laboratory studies showed total cholesterol > 300 mg/dL.

o Multiple lipid profiles since that performed (details incomplete):

Total Cholesterol 350 – 420 mg/dLo No medical therapy to date.

o Diet is a described as “low fat” diet.

o Exercise consist of playing lacrosse and cross country running 75 minutes of sustained physical activity, 5 times per week.

Case MGCase MG

Past Medical History: HyperlipidemiaCurrent Medications: None

Family History: Father – hyperlipidemia (elevated TC, TG)CHD (CABG x 4 at age 40)

Mother – hyperlipidemia (elevated TC)

No information regarding other family membersNo siblings

Review of Systems: Unremarkable, Weight unchanged x 6 months

Case MGCase MG

PE: BP 118/74 Pulse 68 Wt 146.4 lb Ht 68.5” Waist 30” BMI 21.9Otherwise unremarkable

Case MGCase MG

Baseline


TSH, LFT, FBS, Creatinine all WNL

“Low Fat” DietExercise 75 Minutes, 5 x week




Apo B > 75 mg/dL

Apo B < 75 mg/dL

TC:Apo B > 2.4

TC:Apo B < 2.4


VLDL LDL VLDL + LDL

NormoTG< 133 mg/dL

TG:Apo B > 8.8


TG:Apo B < 8.8

HyperTG> 133 mg/dL

NomoTG> 133 mg/dL


Hyper TG> 133 mg/dL

Apo B = 205 mg/dL PrimaryCauses

SecondaryCauses

TG = 163 mg/dL

Case MGCase MGWhat Lipoprotein Abnormality Is Present?What Lipoprotein Abnormality Is Present?

■ FCH■ β-Sitosterolemia ■ DM2

■ Metabolic syndrome■ Abdominal obesity■ Nephrotic syndrome■ Cholestasis■ SLE, PCOS, CAPD■ HIV (HAART)■ Glucocorticoids■ Antipsychotic drugs■ Pregnancy 3rd trimester

Nomogram to Diagnose Familial Combined HyperlipidemiaNomogram to Diagnose Familial Combined Hyperlipidemia

Adapted from Veerkamp MJ, et al. Circulation 2004;109:2980-2985.

Total Cholesterol and Triglyceride PercentilesNational Health and Nutrition Examination Survey 1999‐2006Total Cholesterol and Triglyceride PercentilesNational Health and Nutrition Examination Survey 1999‐2006

Total Cholesterol 1(mg/dL)

Percentiles

White Male Age 10th 25th 50th 75th 90th 95th

12‐17 122 136 154 174 195 212Patient MG 311 (99th percentile)

Triglyceride 2(mg/dL)

Percentiles

White Male Age 10th 25th 50th 75th 90th 95th

17 45 58 80 114 164 210Patient MG 163 (90th percentile)

1. Circulation. 2009;119:1108-11152. J Pediatrics 2009;155:S6.e15-26

163 mg/dL90th

7 points

311 mg/dL99th 4 points

205 mg/dL 5.5 points

16.5 points

Nomogram to Diagnose Familial Combined HyperlipidemiaNomogram to Diagnose Familial Combined Hyperlipidemia

Adapted from Veerkamp MJ, et al. Circulation 2004;109:2980-2985.

10 year versus lifetime assessment?



(CIMT)C. Other testing?

Case MGCase MGWhat Is The Patients Cardiovascular Risk?What Is The Patients Cardiovascular Risk?

Additional Results:hs-CRP = 0.46

CIMT = mean CIMT 0.636, Max CIMT 0.7371.523 mm plaque L Bulb, 1.601 mm plaque R Bulb

Lp(a) = 10LDL-P = > 3500 nmol/L

Absorptive Biomarkers = HyperabsorberCampesterol (5.4 ug/mL), Sitosterol (4.5 ug/mL), Cholestanol (4.2 ug/mL)

Lifetime CHD Risk = Very High Risk

Case MGCase MGWhat Is The Patients Cardiovascular Risk?What Is The Patients Cardiovascular Risk?


Goals: Baseline:

LDL-C: < 70 mg/dL 241 mg/dLnon HDL-C: < 100 mg/dL 274 mg/dLTG: < 150 mg/dL 163 mg/dLOptionalLDL-P: < 800 nmol/L > 3500 nmol/L

Case MGCase MGWhat Are The Appropriate Targets of Therapy?What Are The Appropriate Targets of Therapy?

Therapeutic Lifestyle Changes?

Pharmacologic Therapy?

Case MGCase MGWhat Management Options Should Be Considered?What Management Options Should Be Considered?


Therapeutic Lifestyle ChangesMediterranean Eating Patternlow saturated fat, low refined carbohydrates

Maintain Exercise


Rosuvastatin 20mg daily



Goals: Baseline: 3 months(Wt stable)

LDL-C: < 70 mg/dL 241 mg/dL 104 mg/dLnon HDL-C: < 100 mg/dL 274 mg/dL 130 mg/dLTG: < 150 mg/dL 163 mg/dL 104 mg/dLOptional LDL-P: < 800 nmol/L >3500 nmol/L 1992 nmol/L

Case MG

Response to Therapy

Case MG

Response to Therapy

Therapy

Baseline 3 Month

Rosuvastatin20 mg

TLC (Wt Stable)


TG (mg/dL) 163 129HDL-C (mg/dL) 37 45




LDL-P (nmol/L)[Goal < 800 nmol/L] > 3500 1992


Summary Case MGSummary Case MG




Maintain Exercise


Therapy

Baseline 3 Month

Rosuvastatin20 mg

TLC (Wt Stable)

3 Month

Rosuvastatin20 mg

Ezetimibe 10 mg

TLC (Wt Stable)

Total-C (mg/dL) 311 175 93

TG (mg/dL) 163 129 79HDL-C (mg/dL) 37 45 45

LDL-C (mg/dL) [Goal < 70 mg/dL] 241 104 32


Non HDL-C[Goal < 100 mg/dL] 274 104 48

LDL-P (nmol/L)[Goal < 800 nmol/L] > 3500 1992 704



37 year-old male presents for evaluated of hypercholesterolemia.

Patient first became aware of abnormal serum lipids at approximately age 30 when laboratory studies showed total cholesterol > 200 mg/dL.

o Rare lipid profiles performed since that time (details unknown).

o No medical therapy to date.o Diet is a described as “moderation” diet.

o Exercise consist of 75 minutes of sustained physical activity, 5-7 times per week. Patient is an Army Ranger.

Case PKCase PK

Past Medical History: Hyperlipidemia

Current Medications: NoneFamily History: Father – CHD (stent x 2 at age 45)

Paternal GF – CHD (fatal MI age 48)

Information regarding siblings unknownReview of Systems: Unremarkable,

Weight unchanged x 6 months

Case PKCase PK

PE: BP 128/74 Pulse 62 Wt 205 lb Ht 75.5” Waist 35” BMI 25.3Otherwise unremarkable

Case PKCase PK

Baseline


TSH, LFT, FBS, Creatinine all WNL

“Moderation” DietExercise 75 Min, 5-7 x week




Apo B > 75 mg/dL

Apo B < 75 mg/dL

TC:Apo B > 2.4

TC:Apo B < 2.4


VLDL LDL VLDL + LDL

NormoTG< 133 mg/dL

TG:Apo B > 8.8


TG:Apo B < 8.8

HyperTG> 133 mg/dL

NomoTG> 133 mg/dL


Hyper TG> 133 mg/dL

Apo B = 103 mg/dLTG = 123 mg/dL

Case PKCase PKWhat Lipoprotein Abnormality Is Present?What Lipoprotein Abnormality Is Present?

1 Major Risk Factor (family history)10-year Framingham Risk Score = 2.8% (low risk)



(Coronary Calcium Score, CIMT)C. Other testing?

Case PKCase PKWhat Is The Patients Cardiovascular Risk?What Is The Patients Cardiovascular Risk?

1 Major Risk Factor (family history)10-year Framingham Risk Score = 2.8% (low risk)

Additional Results:

hs-CRP = 2.710-year Reynolds Risk Score = 3.6% (low risk)

CIMT = mean CIMT 0.582, Max CIMT 0.764 (unremarkable)1.723 mm plaque L Bulb, 2.201 mm plaque RICA

Lp(a) = 270

LDL-P = 1580 nmol/L


Case PKCase PKWhat Is The Patients Cardiovascular Risk?What Is The Patients Cardiovascular Risk?


Goals: Baseline:

LDL-C: < 70 mg/dL 129 mg/dLnon HDL-C: < 100 mg/dL 154 mg/dLTG: < 150 mg/dL 123 mg/dLOptionalLDL-P: < 800 nmol/L 1580 nmol/L

Case PKCase PKWhat Are The Appropriate Targets of Therapy?What Are The Appropriate Targets of Therapy?

Therapeutic Lifestyle Changes?

Pharmacologic Therapy?

Case PKCase PKWhat Management Options Should Be Considered?What Management Options Should Be Considered?



Maintain Exercise


Simvastatin 20mg dailyNiaspan 1000mg daily



Goals: Baseline: 4 months(15# Wt Loss)

LDL-C: < 70 mg/dL 129 mg/dL 89 mg/dLnon HDL-C: < 100 mg/dL 154 mg/dL 111 mg/dLTG: < 150 mg/dL 123 mg/dL 69 mg/dLOptional LDL-P: < 800 nmol/L 1580 nmol/L 792 nmol/L

Case PK

Response to Therapy

Case PK

Response to Therapy

Therapy

Baseline 4 Month

Simvastatin20 mg

Niaspan1000 mg

TLC (15# Wt Loss)


TG (mg/dL) 123 69HDL-C (mg/dL) 55 48




LDL-P (nmol/L)[Goal < 800 nmol/L] 1580 792






Maintain Exercise


o Type III Dyslipoproteinemia, Metabolic Syndrome. o Apo E2/E2 and “second hit” resulting in increased VLDL (insulin

resistance)

o Familial Combined Hyperlipidemia, Sterol Hyperabsorption

o FCH – mixed overproduction / clearance defect

Increased apoB containing lipoproteins that may manifest as one of 3 lipid phentypes (high TG, high Cholesterol, both high)

o Hyperabsorption of plant sterols / stanols

o Elevated Lp(a) with relative elevation of LDL particle number

Case RYCase RY

Case MGCase MG

Case PKCase PK

SummarySummary

18-Cromwell Cases NLA with Summary Baltimore Onsite 9-21-13 · CAPD HIV (HAART) Glucocorticoids...

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Transcript of 18-Cromwell Cases NLA with Summary Baltimore Onsite 9-21-13 · CAPD HIV (HAART) Glucocorticoids...