`
`Case Report/Case Series
`Severe Hypertriglyceridemia With Pancreatitis
`Thirteen Years’ Treatment With Lomitapide
`
`Frank M. Sacks, MD; Maxine Stanesa, PA-C; Robert A. Hegele, MD
`
`IMPORTANCE Recurrent pancreatitis is a potentially fatal complication of severe
`hypertriglyceridemia. Genetic defects and lifestyle risk factors may render this condition
`unresponsive to current treatments.
`
`OBSERVATIONS We report this first case of long-term management of intractable near-fatal
`recurrent pancreatitis secondary to severe hypertriglyceridemia by a novel use of lomitapide,
`an inhibitor of microsomal triglyceride transfer protein, recently approved for treatment of
`familial homozygous hypercholesterolemia. The patient had been hospitalized many times
`for pancreatitis since age 15 years. Her serum triglyceride level averaged 3900 mg/dL while
`she received therapy with approved lipid drugs. She is homozygous for a coding mutation
`(P234L) in lipoprotein lipase, leaving her unable to metabolize triglycerides in chylomicrons
`and very low density lipoproteins (VLDL). Lomitapide reduces the secretion of chylomicrons
`and VLDL. Lomitapide, which was started when she was 44 years old after near-fatal
`pancreatitis, lowered her fasting triglyceride level from greater than 3000 mg/dL to a mean
`(SD) of 903 (870) mg/dL while she received 30 mg/d and to 524 (265) mg/dL while she
`received 40 mg/d; eliminated chronic abdominal pain; and prevented pancreatitis. However,
`fatty liver, present before treatment, progressed to steatohepatitis and fibrosis after 12 to 13
`years.
`
`CONCLUSIONS AND RELEVANCE Lomitapide prevented pancreatitis in severe intractable
`hypertriglyceridemia but at a potential long-term cost of hepatotoxicity.
`
`JAMA Intern Med. 2014;174(3):443-447. doi:10.1001/jamainternmed.2013.13309
`Published online December 23, 2013.
`
`Author Affiliations: Department of
`Nutrition, Harvard School of Public
`Health, Boston, Massachusetts
`(Sacks); Channing Division of
`Network Medicine, Brigham and
`Women’s Hospital, Boston,
`Massachusetts (Sacks); Harvard
`Medical School, Boston,
`Massachusetts (Sacks); Harvard
`Vanguard Medical Associates,
`Boston, Massachusetts (Stanesa);
`Robarts Research Institute, London,
`Ontario, Canada (Hegele).
`Corresponding Author: Frank M.
`Sacks, MD, Department of Nutrition,
`Harvard School of Public Health, 665
`Huntington Ave, Boston, MA 02115
`(fsacks@hsph.harvard.edu).
`
`R ecurrent pancreatitis is a severe and potentially fatal
`
`complication of hypertriglyceridemia.1-3 A triglycer-
`ide level greater than 2000 mg/dL is defined as “very
`severe hypertriglyceridemia”4 because these levels can cause
`pancreatitis.1-4 A fasting triglyceride level of 1000 to 2000
`mg/dL is defined as “severe hypertriglyceridemia” and car-
`ries a risk of pancreatitis because after eating, triglyceride lev-
`elsmayriseabove2000mg/dL.(Toconverttriglyceridestomil-
`limoles per liter, multiply by 0.0113.)
`Severeandveryseverehypertriglyceridemiacanbecaused
`by several genetic defects that impair metabolism by lipopro-
`tein lipase of triglycerides in chylomicrons and very low den-
`sity lipoproteins (VLDL).5 This is also called familial chylomi-
`cronemia (type 1 dyslipidemia). Treatments that increase
`metabolism of triglycerides by lipoprotein lipase, such as fi-
`brates or omega-3 fatty acids, are ineffective. Microsomal tri-
`glyceride transfer protein (MTP) transfers triglycerides and
`other lipids to apolipoprotein B48 in the enterocyte and apo-
`lipoprotein B100 in the hepatocyte, a necessary step to start
`the assembly of the lipid-protein complex in the enterocyte
`that will become a chylomicron or in the hepatocyte to be-
`come a VLDL or low-density lipoprotein (LDL).6 Genetic defi-
`
`ciency of MTP causes abetalipoproteinemia, characterized by
`very low plasma levels of triglycerides.6 Thus, MTP inhibitors
`could substantially lower plasma triglyceride levels by inhib-
`iting the formation and secretion of triglyceride-rich lipopro-
`teins.
`
`Report of a Case
`Clinical History Before Treatment With MTP Inhibition
`The patient was first hospitalized for pancreatitis at age 15
`years. She was treated with a low-fat diet; gemfibrozil, 1200
`mg; omega-3 fatty acids; and niacin, singly or in combina-
`tion; without benefit. She had had pancreatitis during each
`of her 3 pregnancies, at ages 23, 33, and 34 years, 1 of which
`ended in miscarriage. For the next 11 years, she experienced
`chronic abdominal pain, and recurrent pancreatitis requir-
`ing 12 hospitalizations, in spite of maximal dietary and drug
`treatment. The mean (SD) triglyceride level on hospital
`admission, not necessarily fasting, was 3570 (1619) mg/dL
`(median, 3179 mg/dL for 12 hospitalizations). During the last
`1 to 2 years of this period, the patient’s chronic abdominal
`
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`Research Case Report/Case Series
`
`Severe Hypertriglyceridemia With Pancreatitis
`
`Genetic and Phenotypic Diagnosis
`Direct sequencing of the patient’s genomic DNA revealed ho-
`mozygosity for the coding missense mutation (P234L) in the
`LPL gene producing noncatalytically active lipoprotein li-
`pase (LpL).7 The LPL P234L mutation has been found in Chi-
`nese persons in China8 and in French Canadians.7 The pa-
`tient’sethnicityisChinese.Nootherpotentialculpritmutations
`were found in coding regions, intron-exon boundaries and pro-
`moters of APOC2, APOA5, LMF1, and GPIHBP1 genes.
`HerplasmaLpLmassconcentrationswereelevated(mono-
`mers, 1010 ng/mL [reference range, 150-300 ng/mL]; and dim-
`ers, 150 ng/mL [reference range, 50-100 ng/mL]),9 consistent
`with the diagnosis of functionally defective LpL. The plasma
`apolipoprotein CII concentration was approximately 10 times
`the reference range (35 mg/dL [reference range, 1.6-4.2 mg/
`dL]).
`The patient’s mean serum fasting lipid levels just prior to
`lomitapide treatment were as follows: triglyceride level, 3109
`mg/dL; LDL cholesterol (LDL-C) level, 63 mg/dL; high-
`density lipoprotein cholesterol (HDL-C) level, 29 mg/dL; and
`apolipoprotein B level, 745 mg/dL (reference range, <120 mg/
`dL). Apolipoprotein B100 and B48 levels were both elevated.
`(To convert LDL-C and HDL-C to millimoles per liter, multi-
`ply by 0,0259; to convert apolioprotein to grams per liter, mul-
`tiply by 0.01.)
`One of the patient’s brothers also has severe hypertriglyc-
`eridemia and recurrent pancreatitis. Five other siblings have
`moderate hypertriglyceridemia but without pancreatitis, sug-
`gesting that at least some of them may be heterozygous for the
`LPL P234L mutation. Her parents’ lipid levels are unknown.
`
`Treatment With MTP Inhibition
`An emergency investigational new drug use and institutional
`review board approval for lomitapide were granted. Written
`informed consent was received. On June 7, 1999, other lipid-
`loweringtherapywasstopped,andtreatmentwasinitiatedwith
`lomitapide, which was the first use of an MTP inhibitor for hy-
`pertriglyceridemia.
`The lomitapide dose was titrated to balance the triglycer-
`ide-lowering effect with avoidance of diarrhea presumably
`caused by fat malabsorption (Figure 1). During the first year
`of treatment, the patient’s fasting triglyceride level while re-
`ceiving the 12.5 mg/d dose averaged 2110 mg/dL; while receiv-
`ing the alternating 12.5 mg/d and 25 mg/d dose regimen, 1416
`mg/dL; and while receiving the 25 mg/d dose, 371 mg/dL
`(Figure 1). A 6-month trial of adding fenofibrate, 200 mg/d, to
`lomitapide, 12.5 mg/d, in an attempt to control the hypertri-
`glyceridemia with a lower dose of lomitapide was a failure
`(Figure 2). In 2009, Aegerion reformulated lomitapide into
`20-mg and 40-mg capsules. The patient’s fasting triglyceride
`levels during treatment with the 20 mg/d dose averaged 1604
`mg/dL;duringtreatmentwithalternating20mg/dand40mg/d
`dose regimen, 903 mg/dL; and during treatment with 40 mg/d
`dose, 524 mg/dL (Figure 2). Her hematocrit level range in-
`creased from a range of 26% to 34% to a range of 38% to 40%
`after the fifth year.
`To date, the patient has been treated with lomitapide for
`13 years. She has had 3 brief uncomplicated hospitalizations
`
`Figure 1. Serum Fasting Triglyceride Concentrations at Baseline (B) and
`During the First Year of Treatment With Lomitapide
`
`Start
`Lomitapide
`
`12.5/25 mg/d
`
`12.5/25 mg/d
`
`Discontinued
`
`12.5 mg/d
`
`25 mg/d
`
`B
`
`1
`
`2
`3
`4
`5
`8
`7
`6
`Months After Starting Lomitapide Treatment
`
`9
`
`10
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`Serum Triglyceride Concentrations, mg/dL
`
`The dose of lomitapide was adjusted to balance efficacy and tolerability. The
`patient’s triglyceride level when receiving 12.5 mg/d averaged 2110 mg/dL,
`when receiving the alternating dose regimen of 12.5 mg/d and 25 mg/d
`averaged 1416 mg/dL, and when receiving 25 mg/d averaged 371 mg/dL.
`Discontinued indicates temporary cessation of lomitapide. (To convert
`triglycerides to millimoles per liter, multiply by 0.0113.)
`
`pain worsened in intensity and duration, seriously damag-
`ing her ability to live normally. At age 44 years, she experi-
`enced a near-fatal episode of pancreatitis complicated by
`hypotension and acute respiratory distress syndrome that
`required intubation. A pancreatectomy was recommended
`as preventive treatment but was deferred to permit addi-
`tional attempts at medical treatment. Three months later,
`pancreatitis returned, and she was admitted to the hospital
`with a serum triglyceride level of 4840 mg/dL.
`
`Laboratory and Clinical Evaluations Before Treatment
`With Lomitapide
`The patient’s fasting serum triglyceride levels were usually
`higher than 2000 mg/dL. Her plasma was grossly lipemic.
`Additional findings were lipemia retinalis, anemia (hemato-
`crit, 26%-34%), thrombocytopenia (platelet count, 100 000
`cells/μL), and leucopenia (white blood cell count, 2000-
`4000/μL). A bone marrow biopsy specimen taken at age 31
`years showed 40% replacement with macrophage-foam
`cells. Abdominal ultrasonographic findings repeatedly
`showed fatty liver and splenomegaly. Computed tomo-
`graphic (CT) scans showed no hepatomegaly or other liver
`abnormality. Serum alanine aminotransferase (ALT) and
`aspartate aminotransferase (AST) levels were usually within
`reference range. The patient did not have diabetes mellitus;
`her body weight was normal, with a body mass index, calcu-
`lated as weight in kilograms divided by height in meters
`squared, of 21 to 22; and results from thyroid and renal tests
`were normal. She rarely drank alcoholic beverages. (To con-
`vert hematocrit to a proportion of 1, multiply by 0.01; to
`convert platelets to ×109/μL, multiply by 1.0; to convert
`white blood cell count to ×109/μL, multiply by 0.001.)
`
`444
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`Severe Hypertriglyceridemia With Pancreatitis
`
`Case Report/Case Series Research
`
`Figure 2. Serum Fasting Triglyceride (TG) Concentrations During Years 2 to 13 of Treatment With Lomitapide
`
`Lomitapide only
`*Lomitapide, 12.5 mg/d + fenofibrate
`
`12.5 + Fenofibrate*
`
`12.5/25 to 25
`mg/d
`
`12.5
`mg/d
`
`12.5
`mg/d
`
`25
`mg/d
`
`12.5/25
`mg/d
`
`25 mg/d
`
`20-40 mg/d
`
`PP
`
`P
`
`1
`
`2
`
`3
`
`4
`
`5
`
`7
`8
`6
`Years During Treatment
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`4500
`
`4000
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`Serum Triglyceride Concentrations, mg/dL
`
`0
`
`B
`
`Each episode of pancreatitis (P) is defined as brief uncomplicated
`hospitalization associated with not taking the drug or exceptionally high dietary
`fat intake (The 2 P’s close to each other are simply 2 pancreatitis episodes that
`occurred at the times indicated on the x-axis). At year 4, a 6-month trial of
`adding fenofibrate, 200 mg/d, to lomitapide, 12.5 mg/d, to try to control the
`hypertriglyceridemia on a lower dose of lomitapide was a failure. The patient’s
`mean serum TG level was 3175 mg/dL (range, 2525-3880 mg/dL; N = 4 TG
`tests) with the combination, compared with 2345 mg/dL (range, 1041-3600
`mg/dL; N = 6 TG measurements) during treatment with lomitapide, 12.5 mg/d.
`
`This time period is indicated by vertical gray columns. In the 10th year,
`lomitapide was reformulated into 20- and 40-mg capsules. The mean (SD) TG
`levels during treatment with 20 mg/d was 1604 (1030) mg/dL (median, 1331
`mg/dL; N = 13 TG measurements); during treatment with the alternating dose
`of 20 mg/d and 40 mg/d, 903 (870) mg/dL (median, 703 mg/dL; N = 10 TG
`measurements); and during treatment with the 40-mg/d dose, 524 (265)
`mg/dL (median, 542 mg/dL; N = 4 TG measurements). B indicates baseline. (To
`convert TG to millimoles per liter, multiply by 0.0113.)
`
`for pancreatitis during the third, fourth, and seventh years of
`treatment associated with either having no lomitapide or high
`dietary fat intake during visits to her family in China.
`
`Hepatic Toxicity of Lomitapide
`The patient’s serum ALT and AST levels during the initial 6 to
`7 years of lomitapide treatment were usually within refer-
`ence range, increasing thereafter (Figure 3). Her alkaline phos-
`phatase levels were within reference range before treatment
`and through 12 years of lomitapide treatment. In the 13th year,
`the alkaline phosphatase level increased to 130 and 143 U (up-
`per limit of reference range, 125 U) (to convert alkaline phos-
`phatase to microkatals per liter, multiply by 0.0167). Her serum
`bilirubinandalbuminlevelswerewithinreferencerangebefore
`and during lomitapide treatment. Ultrasonographic examina-
`tionsshowedfattyliver,andfindingsfromhepaticCTandmag-
`netic resonance image scans were normal. Results of a liver
`biopsy at 1 year showed marked steatosis without necrosis, in-
`flammation, fibrosis, or stainable iron; at 3 years showed se-
`vere microvesicular and macrovesicular steatosis, minimal
`lobular inflammation, mild cholestasis, without necrosis, fi-
`brosis, or stainable iron; at 5 years showed marked predomi-
`nantly macrovesicular steatosis without inflammation or fi-
`brosis, and trace amounts of stainable iron; and at 8.5 years
`showed marked predominantly macrovesicular steatosis and
`
`mild steatohepatitis but no clinically significant fibrosis or
`stainable iron. The results from the most recent biopsy at 13
`years showed severe mixed large- and small-droplet steatosis
`involving more than 66% of the core biopsy (NASH activity
`score, 3); frequent ballooning degeneration (score, 2); mild por-
`tal and septal and mild to focally moderate lobular mixed in-
`flammation (score, 2); and portal, septal, and sinusoidal fibro-
`sis(atleaststage3fibrosis,focallyearlystage3-4);andnegative
`results from an iron stain.
`Progression of fatty liver to hepatitis and fibrosis pre-
`sents a therapeutic dilemma.10 In lipoprotein lipase defi-
`ciency, large nascent triglyceride-rich chylomicrons and VLDL
`cannot be metabolized to smaller lipoproteins that can pass
`through the sinusoidal endothelial cell fenestrations to the he-
`patocytes that clear them from the circulation.11 Instead, these
`large lipoproteins are taken up by the reticuloendothelial sys-
`tem in the liver, spleen, and bone marrow. Prior to lomitapide
`treatment, the patient did not have an increased serum trans-
`aminaselevelorhepatomegaly.Thefattyliverrepeatedlyfound
`on ultrasonography could have represented lipid-laden sinu-
`soidal macrophages (Kupfer cells), suggested by their preva-
`lence in the bone marrow. A liver biopsy was not performed
`before lomitapide treatment. In contrast, inhibition of he-
`patic MTP decreases a principal means that hepatocytes use
`to reduce their fat content.12 The MTP inhibition in hypercho-
`
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`Research Case Report/Case Series
`
`Severe Hypertriglyceridemia With Pancreatitis
`
`Figure 3. Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) at Baseline and During 13 Years’ Treatment With Lomitapide
`
`Moderate steatohepatitis, necrosis, fibrosis
`
`Steatosis;
`no inflammation or fibrosis
`
`Mild steatohepatitis
`
`B
`
`1
`
`2
`
`3
`
`4
`5
`7
`8
`9
`10
`6
`Years of Lomitapide Treatment
`
`11
`
`12
`
`13
`
`14
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`B
`
`Serum AST Levels, u/L
`
`Moderate steatohepatitis, necrosis, fibrosis
`
`Steatosis;
`no inflammation or fibrosis
`
`Mild steatohepatitis
`
`B
`
`1
`
`2
`
`3
`
`4
`5
`7
`8
`9
`10
`6
`Years of Lomitapide Treatment
`
`11
`
`12
`
`13
`
`14
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`A
`
`Serum ALT Levels, u/L
`
`The upper limits of normal were 40 U/L for ALT (A) and 35 U/L for AST (B).
`Findings of the liver biopsy described in more detail in the subsection titled
`
`“Hepatic Toxicity of Lomitapide.” B indicates baseline. (To convert ALT and AST
`to microkatals per liter, multiply by 0.0167.)
`
`lesterolemia increases liver transaminases and hepatic fat
`content.13,14 Therefore, the hepatic pathophysiologic char-
`acteristics of lomitapide toxicity differ from those of lipo-
`protein lipase deficiency, and it is possible that the 2 sepa-
`rate effects may adversely interact. No other patient has
`been treated with lomitapide for more than 5 years, and
`thus the long-term effects of the drug in lipoprotein lipase
`deficiency as well as in familial hypercholesterolemia need
`to be studied carefully.
`
`Discussion
`Now that lomitapide is available in the United States for treat-
`ment of familial homozygous hypercholesterolemia, physi-
`cians may consider it to treat pancreatitis caused by severe hy-
`pertriglyceridemia. However, lomitapide is not approved for
`this “off-label” use, and it may be available only on a named
`patient compassionate use basis with approval of the manu-
`
`facturer and the relevant health authorities and ethics com-
`mittees. We suggest these criteria: (1) pancreatitis associated
`with severe hypertriglyceridemia, (2) failure of intensive diet
`and drug treatment to prevent episodes of pancreatitis, and
`(3) no active hepatitis or hepatic fibrosis.
`We do not recommend using lomitapide in patients who
`have severe hypertriglyceridemia without pancreatitis be-
`cause many of them never develop pancreatitis. A recent clini-
`cal case series reported that 16% of patients who had triglyc-
`eride levels higher than 1772 mg/dL had pancreatitis.15
`Maximum efforts to encourage dietary adherence must be
`made, especially because dietary fat will make the lomi-
`tapide less effective at a given dose and more prone to cause
`diarrhea. We emphasize that we used lomitapide in a desper-
`ateclinicalsituationinwhichthepatientatanytimecouldhave
`a fatal attack of pancreatitis. If physicians choose to use lomi-
`tapide in such patients, they must report their results so ex-
`perience will accumulate to understand the benefits and long-
`term risks.
`
`ARTICLE INFORMATION
`Accepted for Publication: October 28, 2013.
`Published Online: December 23, 2013.
`doi:10.1001/jamainternmed.2013.13309.
`Author Contributions: Dr Sacks had full access to
`all of the data in the study and takes responsibility
`for the integrity of the data and the accuracy of the
`data analysis.
`Study concept and design: Sacks.
`Acquisition of data: Sacks, Stanesa, Hegele.
`Analysis and interpretation of data: Sacks, Stanesa,
`Hegele.
`Drafting of the manuscript: Sacks.
`Critical revision of the manuscript for important
`
`intellectual content: All authors.
`Statistical analysis: Sacks, Stanesa.
`Administrative, technical, or material support:
`Hegele, Stanesa.
`Study supervision: Sacks.
`Conflict of Interest Disclosures: Dr Sacks has
`consulted for companies that develop or market
`drugs for dyslipidemia (Merck, ISIS, Genzyme,
`Sanofi, Lilly, Roche), given lectures (AstraZeneca)
`and was an expert witness (Abbott). Dr Hegele is a
`consultant and speaker for Abbott, Merck, Amgen,
`Valeant Pharma, Tribute Pharma, and Sunovion and
`was a consultant for Aegerion Pharmaceuticals. No
`other disclosures are reported.
`
`Additional Information: Dr Sacks treated the
`patient and obtained the investigational drug. Ms
`Stanesa has been the patient’s primary care
`provider during the duration of treatment. Dr
`Hegele directed the genotyping investigation.
`Additional Contributions: We thank Rene Belder,
`MD, formerly of Bristol Myers Squibb, for providing
`the drug and treatment protocol for the US Food
`and Drug Administration’s Investigational New Drug
`application; Daniel Rader, MD, for supporting our
`efforts to continue treatment with lomitapide and
`for comments on a draft of the manuscript; and
`Aegerion Pharmaceuticals for continuing to provide
`the drug. We also acknowledge the assistance of
`
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`Aegerion in making the figures in the manuscript
`from data provided by Dr Sacks and for engaging
`Richard S. Perry, PharmD, to review and summarize
`the literature.
`
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