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Niacin induced coagulopathy as a manifestation of occult liver injury.

Introduction

Niacin (nicotinic acid) is the oldest and one of the most effective lipid-lowering agents currently available. Reduction in cardiovascular events and total mortality has been documented with niacin use. (1,2) Statins have evolved to first line therapy for hyperlipidemia due to efficacy and relatively low adverse drug reactions. Niacin use has been somewhat limited by the adverse reaction of flushing and reports of infrequent but serious hepatotoxicity, including fulminant hepatic failure. (3-5) Nonetheless, niacin continues to have a significant niche in the management of more pronounced forms of hyperlipidemia, and in patients intolerant of statins. Currently, Niaspan is the only extendedrelease FDA approved niacin, and is the most commonly used form. This preparation was developed to minimize flushing and hepatotoxicity seen with immediate-release (Niacor), and "sustained-release" forms, the latter being of different composition and not FDA approved, but currently sold as dietary supplements. (6,7)

There have been a small number of reported cases showing isolated reversible coagulopathy without overt hepatic injury in patients on niacin, both sustained and immediate release. (8-10) This type of presentation is felt to represent a form of occult hepatotoxicity relating to niacin. In addition, "extraordinary" decreases in lipoproteins have been reported in some patients, thought to indicate impairment of hepatic protein synthesis as a manifestation of liver toxicity. (10,11)

Our case of a patient on extended release niacin revealed dramatic reversible decreases in hepatic clotting factors, lipoproteins, and other proteins, without elevation of hepatic enzymes or overt hepatic injury.

Presentation of Case

A 61 year old male with a history of coronary artery disease, hyperlipidemia, Gilbert syndrome, and hypothyroidism had routine laboratory studies which revealed coagulation abnormalities. This precipitated further testing. He had no prior history of hematologic or hepatic disease.

He felt subjectively well. He consumed one drink of alcohol per day. Physical exam was normal. Medications included extended release niacin (Niaspan), 2000 mg daily (used for approximately 4 years), atorvastatin 40 mg daily, aspirin 81 mg daily, fish oil 3000 mg daily, amitriptyline 50 mg daily, levothyroxine 125 mcgm daily and multivitamins.

Initial laboratory and imaging studies follow: Hemoglobin & WBC normal, platelets 117,000/ cu mm (repeat 231,000 mg/dL), prothrombin time 14.2 seconds (INR 1.5) and 16.6 seconds (INR 1.8) seven days post vitamin K. PTT 30 seconds (21-30 s), thrombin time 26 seconds (16-25 s), fibrinogen 162 mg/dL (200-375), total bilirubin 1.4 mg/dL, direct bilirubin 0.3 mg/dL. Hepatitis panel was negative. Ultrasound of the liver and spleen was negative.

Niacin was discontinued, with subsequent resolution of laboratory abnormalities in one month.

Comparison of the most relevant laboratory studies before and after discontinuation of niacin is shown in Tables 1 and 2.

Discussion

Although there has been some recent discussion regarding niacin in statin patients already at LDL goal, (12) niacin remains a proven, protective anti-hyperlipidemic medication, particularly in the management of more serious lipid disorders, and when statins are not tolerated. (1,2) Niacin is known to have potential for infrequent, generally dose related hepatocellular injury, usually reported as fulminant. (3-5) In addition, there have been reports of coagulopathy relating to decreased production of hepatically derived clotting factors without overt hepatic injury, i.e. minimal or no elevations in aminotransferases. (8-10) Extremely low lipoproteins also have been reported in some patients taking niacin preparations. It has been speculated that such dramatic changes in LDL/HDL may not actually reflect achievement of desirable lipoprotein levels through altered secretion, but rather impaired synthesis of apoproteins. (10,11) Other reversible decreases in laboratory parameters (e.g. total protein, albumin, and fibrinogen) may substantiate the impression of altered protein synthesis and may reflect serious ongoing but unapparent hepatic injury.

Our case demonstrates reversible decreases in clotting factors of hepatic origin and marked decrease in hepatic lipoproteins (including HDL), similar to previous reports. Other decreases in hepatic proteins are noted. The elevation of indirect bilirubin reflects Gilbert syndrome, a harmless and unrelated disorder. Aminotransferase levels remained in normal range while on niacin, although slightly higher. We suspect that this patient may have progressed to hepatic failure if niacin had been continued despite surveillance with aminotransferase levels.

Based on these findings and previous reports, patients taking all forms of niacin (particularly in higher doses), should have periodic assessment of prothrombin time, in addition to hepatic enzymes. A detected coagulopathy may have significant clinical consequences (i.e. bleeding), and portend eventual hepatic decompensation. Extremely low levels of lipoproteins may also provide a clue to occult hepatic injury. This appears to be the first case of extended-release niacin associated with this form of evident hepatic impairment.

Conclusion

Extended-release niacin as well as other niacin preparations may suppress hepatic protein synthesis resulting in coagulopathy and other abnormalities without frank elevation of hepatic enzymes. These changes may reflect underlying potentially severe occult hepatic injury. Pharmaceutical marketing for extended-release niacin may result in more frequent reported episodes of this form of toxicity. Prothrombin time should be included with hepatic enzymes in the routine monitoring of patients on niacin.

References

(1.) Canner PL, Berge KG, Wenger NK, et al. Coronary Drug Project Research Group: Fifteen Year Mortality in Coronary Drug Project patients: long term benefit with niacin. J Am Coll Cardiol. 1986:8:12451255.

(2.) Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990:323:1289-1298.

(3.) Hodis HN. Acute hepatic failure associated with low-dose sustained release niacin. JAMA 1990;264(2):181.

(4.) Mullin GE, Greenson JK, Mitchell MC. Fulminant hepatic failure after ingestion of sustained-release nicotinic acid. Ann Intern Med. 1989:111(3):253-255.

(5.) Clementz GL, Holmes AW. Nicotinic acid-induced fulminant hepatic failure. J Clin Gastroenterol 1987;9(5):582-584.

(6.) Guyton JR. Extended release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother 2004;5(6):1385-1397.

(7.) Pieper JA. Overview of niacin formulations: Differences in pharmacokinetics, efficacy, and safety. Am J Health-Syst Pharm. 2003;60:509-514.

(8.) Dearing BD, Lavie CJ, Lohman TP, Genton E. Niacin-induced clotting factor synthesis deficiency with coagulopathy. Arch Intern Med. 1992;152:861-863.

(9.) Coppola A, Brady G, Nord HJ. Niacininduced hepatotoxicity: unusual presentations. South Med J. 1994;87:3032.

(10.) Tato F, Vega GL, Grundy SM. Effects of crystalline nicotinic acid-induced hepatic dysfunction on serum low-density lipoprotein cholesterol and lecithin cholesterol acyl esterase. Am J Cardiol. 1998;81:805-807.

(11.) Gray DR, Morgan T, Chretien SD, et al. Efficacy and safety of controlled release niacin in dyslipoproteinemic veterans. Ann Intern Med 1994;121:252-258.

(12.) The AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med. 2011;DOI:10.1056/oa1107579.

Ehab Haj Ali, MD

Brittain McJunkin, MD

Steven Jubelirer, MD

William Hood, DO

Department of Internal Medicine, West Virginia University Health Sciences Center, Charleston Division, Charleston
Table 1. Laboratory studies before and after discontinuation of
niacin.

 PT PTT TT Fib F II F V FVII F X
 (sec) (sec) (sec) (mg/ (%) (%) (%) (%)
 dL)

On 16.6 30 26 162 36 21 31 56
Niacin
4 wks post 10.7 31 25 247 -- 64 112 -Niacin

 ALT AST T P ALB T C LDL HDL
 (U/L) (U/L) (gm/ (gm/ (mg/ (mg/ (mg/
 dL) dL) dL) dL) dL)

On 44 52 5.9 3.3 79 28 37
Niacin
4 wks post 25 24 6.4 3.9 188 116 53
Niacin

Abbreviations: PT = prothrombin time; PTT = partial thromboplastin
time; TT = thrombin time; Fib = fibrinogen; FII = Factor II; F V =
Factor V; F VII = Factor VII; F X = FactorX; ALT = alanine
aminotransferase; AST = aspartate aminotransferase; TP = total
protein; Alb = albumin; TC = total cholesterol; LDL = low density
lipoprotein; HDL = high density lipoprotein.

Normal values: PT 9.2-11.3 sec; PTT 21.1-32.0 sec; TT 16-25 sec;
Fibrinogen 200-375 mg/dL; Factor II 70-130%; Factor V 60-145%;
Factor VII 50-160%; total protein 6.1-8.0 mg/dL; albumin 3.5-5.0
mg/dL; ALT 17-67 U/L; AST 15-65 U/L.

Table 2. Comparison of pertinent laboratory parameters from 2007
and 2008.

 AST ALT LDL HDL
 (U/L) (U/L) (mg/dL) (mg/dL)

July 2007 on Niacin 29 26 54 56
Nov. 2008 on Niacin 52 44 28 37
Dec. 2008 4 wks post Niacin 24 25 116 53

Abbreviations: AST = aspartate aminotransferase; ALT = alanine
aminotransferase; LDL = low density lipoproteins; HDL = high
density lipoproteins.

No prior coagulation studies were recorded.

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Article Details
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Title Annotation:Scientific Article
Author:Ali, Ehab Haj; McJunkin, Brittain; Jubelirer, Steven; Hood, William
Publication:West Virginia Medical Journal
Article Type:Case study
Geographic Code:1USA
Date:Jan 1, 2013
Words:1505
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