The Impact of Gilbert’s Syndrome on Atherosclerosis

A 51-year-old female with a history of premature coronary heart disease and coronary artery bypass grafting at age 36 was referred for hyperlipidemia. She had untreated low-density lipoprotein cholesterol (LDL-C) >600 mg/dL, a previous cholecystectomy, and non-alcoholic fatty liver. On maximal medical therapy with rosuvastatin 40 mg per day, ezetimibe 10 mg per day, and extended-release niacin 1,000 mg per day, lipid levels remained elevated; LDL apheresis was added. Diagnostic genetic tests showed compound heterozygous familial hypercholesterolemia. On apheresis, her LDL-C on maximal standard therapy exceeded 300 mg/dL, so lomitapide was started at 5 mg per day. Liver-function tests were normal at baseline but bilirubin rose to 3.4 mg/dL after the addition of lomitapide. No symptoms were reported but, out of caution, medications were withheld, bilirubin sub-fractions were obtained and a hepatology consult was obtained. Gilbert’s syndrome (GS) was confirmed. It was noted that indirect bilirubin immediately returned to normal when the patient was off medications. When medications were restarted, total bilirubin returned to 3.0-3.4 mg/dL with indirect bilirubin at 2.2-2.8 mg/ dL and direct bilirubin at 0.6-0.8 mg/dL. No symptoms or complications have arisen eight months after restarting medications.

Discussion

Augustin Gilbert described in 1901 a syndrome of asymptomatic mild jaundice. This syndrome is characterized by the absence of disease or complications, with only an excess level of indirect (unconjugated) bilirubin, which is regarded as merely a benign laboratory abnormality. The hyperbilirubinemia of GS is noted to increase with fasting, stress, and some medications that are metabolized by the liver, including many antibiotics, some oral contraceptives, benzodiazepines, indomethacin, and phenytoin. Smoking decreases serum bilirubin.

Hemoglobin is metabolized by heme-oxygenase to biliverdin, which is converted by biliverdin reductase to bilirubin. Solute carrier anion transporter 1B (SLCO1B1) transports unconjugated bilirubin from the blood into the liver. Mutations of this organic anion transporter increase simvastatin and other statin medication levels, contributing to myalgia. Loss-of-function mutations or drug competition at SLCO1B1 with statins also may increase total and unconjugated bilirubin levels. Glucuronyl transferase conjugates bilirubin with one or two glucuronic acid molecules, rendering it soluble. Conjugated (direct) bilirubin then enters the bile and is excreted. GS is most commonly attributed to a homozygous mutation of glucuronyl transferase at the UGT1A1*28 allele with genotype 7/7. This genotype causes decreased conjugation of bilirubin. Prevalence of this genotype varies widely across populations, with a maximum of 10 percent of Europeans and a minimum of 3 percent of South Asian Islanders manifesting the syndrome.

There are some clinical associations with GS. Gallstones are increased in frequency with GS. Neutropenia and diarrhea can occur in patients with GS on irinotecan chemotherapy for colon cancer. Some investigators have also reported increased fatigue, decreased mental concentration, and nonspecific symptoms affecting the body as a whole in patients with GS. Numerous studies note an inverse association between bilirubin levels and atherosclerosis. In patients with familial hypercholesterolemia, elevated serum bilirubin was associated with a decreased risk for early coronary atherosclerosis. The protective effect of bilirubin was comparable to that conferred by high-density lipoprotein (HDL) cholesterol.1 Results from a meta- analysis of 11 published studies showed an inverse relationship between bilirubin levels and the severity of atherosclerosis.2 Similarly, studies have recognized a direct linear association between low bilirubin levels, atherosclerosis,3 and stroke.4

Various mechanisms have been proposed to explain the beneficial effects of bilirubin on atherosclerosis. Bilirubin acts as an antioxidant in vitro and in vivo. This antioxidant effect has been shown to suppress the oxidation of lipids and lipoproteins, especially LDL. Bilirubin also has some anti-inflammatory properties that can inhibit tumor necrosis factor-a (TNF-a), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1).5 The anti-inflammatory and antioxidant properties of bilirubin may mediate other risk factors that promote atherosclerosis. Bilirubin may also function as an anti-thrombotic agent by reducing oxidative platelet hyper-reactivity, thereby reducing athero-thrombosis.6

More recently, studies have been performed to further characterize the genetic basis for GS. The Framingham Offspring Study showed a strong association between UGT1A1*28 allele genotype 7/7 demonstrating a higher bilirubin level and 1/3 the risk of cardiovascular disease and coronary heart disease versus carriers of the 6 allele. There also was a non-significant trend toward fewer myocardial infarctions. Furthermore, Cox hazard regression analysis with serum bilirubin and UGT1A1*28 revealed that the association with the UGT1A1 polymorphism was not significant when bilirubin was added — raising the possibility that other aspects of hemoglobin metabolism may contribute more significantly to bilirubin levels, even in those with the UGT1A1*28 genotype 7/7.7 An inverse relationship between the UGT1A1*28 allele, bilirubin levels, and cardiovascular disease was discovered in Chinese males.8

Using Mendelian randomization to address confounding variables such as obesity, cholesterol, and blood pressure, UGT1A1*28 homozygotes were associated with higher serum bilirubin, smaller brachial artery diameter, and cold pressor reactivity. This suggests that the benefits of higher bilirubin may affect cardiovascular disease through pathways associated with arterial size such as vasomotor tone, reactivity, and possibly arterial wall structure. 9

In the above case study, our patient was noted to progress from a normal baseline total bilirubin to hyperbilirubinemia with the addition of lomitapide. However, there were no untoward effects secondary to the hyperbilirubinemia with more than one year of therapy. It is noted that our patient had a previous cholecystectomy in accordance with the known higher risk of gallstones in GS. Even with homozygous familial hypercholesterolemia, she has had no further clinical progression of cardiovascular disease after coronary bypass surgery 15 years ago. This may be due, in part, to the protective effect of GS on atherosclerosis.

Future clinical considerations may include recommending a full liver function test with bilirubin level before initiating statin therapy. Full liver function tests are recommended before and during lomitipide therapy. The NLA statin safety liver taskforce noted the value of albumin, prothrombin time and possibly direct bilirubin measurements prior to statin therapy.10 Presently, the FDA recommends “liver enzyme measurements” only before initiating statin therapy and no longer advocates routine monitoring during therapy.11 Given the high prevalence of GS in patients of European heritage and its association with reduced atherosclerosis, measuring the total bilirubin level may contribute to a more thorough cardiovascular risk assessment. At this time, however, routine genetic testing for the UGT1A1*28 genotype is not recommended and does not appear to significantly contribute to patient care. Developing therapies to increase serum bilirubin levels in those with low levels may reduce cardiovascular risk in the future. Disclosure statement: Dr. Trippi has received speaker honoraria from Aegerion Pharmaceuticals Inc., Amarin, LipoScience, Merck & Co. Inc., and Sanofi.

References are listed on page 37 of the PDF.