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More Than Meets the Iris

Submitted by Michael Kuo and Marelle Yehuda

Published Oct 6, 2019

A 16-year-old male presents with xanthomas and lipomas on his elbows, knees, and face.  He has had these xanthomas since he was 4 years old. He underwent excision of the xanthomas on his elbows and knees in the past, but a xanthoma reformed on his left elbow.  He has a family history of a twin brother with similar physical examination findings. His eye examination shows white circular bands on the borders of his irises bilaterally that have been present since he was 2 years old (Figure).  He has small 0.5 cm firm nodules around his eyes bilaterally, a 7 cm x 7 cm firm nodule on his left elbow, and surgical scars from past excisions on his bilateral elbows and knees. He was found with a total cholesterol of 819 and LDL of 764.

Based on his presence of LDL >500, he was diagnosed with homozygous familial hypercholesteremia, and initiated on lipid lowering treatment.  Despite treatment with atorvastatin 80 mg daily, ezetimibe 10 mg daily, and niacin 3000 mg nightly his total cholesterol reached 706 with an LDL of 629.  His clinical course was complicated by asymptomatic bilateral carotid stenosis (<50%). Niacin was later discontinued secondary to flushing side effects, and Lomitapide 5 mg daily was added.  Lomitapide was slowly uptitrated to 30 mg daily. Combined with dietary modification, his total cholesterol lowered to 100 with an LDL of 70.

Questions

1.  What is the first line therapy for lowering LDL in patients presenting with familial hypercholesterolemia?

A  Niacin

B.  Bile acid sequestrants

C.  Statin

D.  Lomitapide

2.  What is the US black box warning for lomitapide?

A. Sudden death

B. Thrombocytopenia

C. Thromboembolic events

D. Hepatotoxicity

Answers:

Question 1. Answer C (Statin).  

Statins are the first line therapy for LDL lowering in familial hypercholesterolemia.  Statins are recommended as the initial drug for all adults with familial hypercholesterolemia and children aged 8 to 10 years old with a treatment goal of ≥50% reduction in LDL from baseline.  Statin therapy is effective in heterozygous familial hypercholesterolemia patients and can be beneficial in homozygous familial hypercholesterolemia patients with some LDL receptor activity.1,6

Question 2.  Answer D (Hepatotoxicity)

Lomitapide has a black box warning for hepatotoxicity and is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) and patients with active liver disease. 5  Lomitapide causes hepatic steatosis with or without concomitant increases in transaminases.  The long-term consequences are unknown. The FDA recommends reduction in alcohol use to no more than 1 drink/day, as this drug may increase hepatic fat or induce liver injury if taken with alcohol.   Caution is advised when this medication is used with other drugs known to cause hepatotoxicity such as methotrexate, tetracyclines, isotretinoin, acetaminophen, amiodarone, and tamoxifen. 5  Additionally, elevations in transaminases were noted in multiple patients during clinical trials with ALT or AST up to 3 times the upper limit of normal.  Initiation of this medication requires frequent monitoring of liver function tests. 5

Discussion:

Familial hypercholesteremia is a genetic disorder that leads to increased cholesterol levels starting from birth that increases life time atherosclerotic cardiovascular disease risk.  These complications stem from a defect in LDL-receptors that leads to an inability to clear LDL from circulation via LDL receptor-mediated endocytosis, thereby driving the serum LDL well above the normal range.1

Familial hypercholesteremia should be suspected in all patients presenting with LDL levels >190.  Patients can have heterozygous or homozygous genotypes, the latter of which is associated with higher LDL levels.  Patients can commonly present with corneal arcus - stromal lipid deposits around the iris - and is often called arcus senilis as this finding can often be found in the elderly patient as a process of normal aging.5

Diagnosis of homozygous familial hypercholesteremia can be made by genetic analysis or fulfillment of phenotypical criteria.  Genetic diagnosis requires two alleles at gene locus for LDLR, APOB, PCKS9, LDLRAP1. Phenotypic diagnosis can be made on the presence of untreated LDL >500 or treated >300, plus one of the following: the presence of cutaneous or tendon xanthomas before age 10 or family history of both parents having evidence of heterozygous familial hypercholesteremia.6  Patients will typically require more than one medication to obtain optimal cholesterol lowering.  Initial treatment consists of a statin medication, but typically a cholesterol absorption inhibitor and niacin must be added.  If cholesterol levels are still refractory to conventional treatments, new pharmacologic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein; mipomersen, an anti-sense oligonucleotide inhibitor of APOB; and evolucomab, a PCSK9 inhibitor.3,4  Lastly, LDL apheresis (akin to ultrafiltration by dialysis) can be done to decrease LDL levels, and, in some countries, hepatic transplantation may be necessary.4

References:

  1. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-79.

  2. Center for Drug Evaluation and Research. “Drug Safety and Availability - Medication Guides.”  Juxtapid (lomitapide) [5/2016 version] Medication Guide. U S Food and Drug Administration Home Page, Center for Drug Evaluation and Research, www.fda.gov/Drugs/DrugSafety/ucm085729.htm.  Accessed 11/22/2017.

  3. Dixon DL, Sisson EM, Butler M, Higbea A, Muoio B, Turner B. Lomitapide and mipomersen: novel lipid-lowering agents for the management of familial hypercholesterolemia. J Cardiovasc Nurs. 2014;29(5):E7-E12.

  4. France M. Homozygous familial hypercholesterolaemia: update on management. Paediatr Int Child Health. 2016;36(4):243-247.

  5. Raj KM, Reddy PA, Kumar VC. Significance of corneal arcus. J Pharm Bioallied Sci. 2015;7(Suppl 1):S14-5.

  6. Turgeon RD, Barry AR, Pearson GJ. Familial hypercholesterolemia: Review of diagnosis, screening, and treatment. Can Fam Physician. 2016;62(1):32-7.

Author Information:

Michael Kuo, M.D., Albert Einstein College of Medicine.  Harbor-UCLA Medical Center, Senior resident in Internal Medicine.

Marelle Yehuda, M.D., Tel Aviv University Sackler Faculty School of Medicine. Lenox Hill Hospital, Hofstra Northwell School of Medicine, Internal Medicine.  Harbor-UCLA Medical Center, Endocrinology. Attending in Endocrinology at Sutter Health Palo Alto Medical Foundation.

 



 

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