new onset severe hypercholesterolemia in a patient with cholestatic liver disease should we treat the lipids

Accepted Manuscript New-onset severe hypercholesterolemia in a patient with cholestatic liver disease Should we treat the lipids? Panteleimon E Papakonstantinou, Eirini Theodoraki, Mairi Koulentaki, John A Papadakis PII: S1109-9666(16)30239-1 DOI: 10.1016/j.hjc.2016.12.009 Reference: HJC 107 To appear in: Hellenic Journal of Cardiology Received Date: 12 October 2016 Revised Date: 12 December 2016 Accepted Date: 23 December 2016 Please cite this article as: Papakonstantinou PE, Theodoraki E, Koulentaki M, Papadakis JA, Newonset severe hypercholesterolemia in a patient with cholestatic liver disease Should we treat the lipids?, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2016.12.009 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Case Report New-onset severe hypercholesterolemia in a patient with cholestatic liver disease Should we treat the lipids? Panteleimon E Papakonstantinoua, Eirini Theodorakib, Mairi Koulentakib, a RI PT John A Papadakisa Hypertension Unit (ESH Excellence Centre), Department of Internal SC Medicine, University Hospital of Heraklion, 71500 Voutes, Heraklion, Crete, Greece Department of Gastroenterology, University Hospital of Heraklion, 71500 M AN U b Voutes, Heraklion, Crete, Greece Panteleimon E Papakonstantinou e-mail: pantelispapakon@gmail.com TE D Eirini Theodoraki e-mail: eirinith25@yahoo.gr Mairi Koulentaki e-mail: mkoulentaki@yahoo.gr EP Corresponding author: John A Papadakis MD, PhD AC C Internist - Clinical Hypertension Specialist EHS R Director in the Department of Internal Medicine Head of Hypertension Unit of the Dept of Internal Medicine(ESH Excellence Centre) University Hospital of Heraklion, 71500 Voutes, Heraklion, Crete ,GREECE Phone: +302810392688 Fax: +302810392359 e-mail: papadakisja@hotmail.com ACCEPTED MANUSCRIPT Key words: cholestasis; cholestatic liver disease; dyslipidemia; ERCP; AC C EP TE D M AN U SC RI PT hypercholesterolemia ACCEPTED MANUSCRIPT Dyslipidemia is one of the major factors of atherosclerotic artery disease1-3 In the presence of high serum cholesterol levels, secondary causes of dyslipidemia should always be excluded4 The most common causes are type diabetes mellitus, obesity, chronic renal failure, nephrotic RI PT syndrome, drugs, hypothyroidism and cholestatic liver diseases5 More specifically, hypercholesterolemia is a common feature of cholestatic syndromes4,6,7 However, cholesterol levels beyond 500 mg/dl rarely occur in SC patients with cholestasis We report a case of new-onset severe hypercholesterolemia in a 39-year-old patient with cholestasis due to M AN U inflammation and stenosis of the common bile duct A 39-year-old male was referred to our outpatient clinic due to severe new-onset of intermittent right hypochondriac pain, jaundice and hypercholesterolemia (total cholesterol of 958 mg/dl, LDL cholesterol of 871 TE D mg/dl) His medical history included alcohol abuse (8 units of alcohol per day) during the last ten years He was an active smoker (20 pack years), his body EP mass index (BMI) was 23.8 kg/m2 and his family history was unremarkable He was not receiving any medication, while he was under fat-free diet AC C Two years previously he suffered an episode of acute pancreatitis He had undergone an Endoscopic retrograde cholangiopancreatography (ERCP), due to a bile duct stenosis, that was negative for dysplasia or malignancy in the cytological examination and a stent was placed which was replaced with a new one three months later The patient’s lipid levels during this (first) hospitalization are presented in table (January 2014) On the second admission, the patient complained of intermittent pain in the right hypochondria for the last seven months On physical examination, ACCEPTED MANUSCRIPT there was jaundice, with no xanthomas or xanthelasmas Τhe thyroid hormones were within normal limits, while there was no evidence for nephrotic syndrome The fasting plasma glucose level was 83mg/dl (reference range: 70-115mg/dl) The laboratory examinations revealed elevated liver enzymes RI PT and hyperbilirubinemia (Table 1, March 2016) The abdominal ultrasound showed sludge in the gallbladder and a dilatation of the common bile duct (1.5cm) due to the presence of two gallstones Anti-mitochondrial antibodies SC (AMA), anti-M2, anti-smooth muscle antibodies (ASMA) and anti-nuclear antibodies (ANA) were negative for primary biliary cirrhosis The patient M AN U underwent a new ERCP, removal of the ductal gallstones and new stenting due to inflammation and stenosis at the lower part of the common bile duct The liver enzymes and the cholesterol level decreased gradually (Table 1, April-June 2016) After a follow-up period of three months, the patient TE D remained symptom-free without evidence of jaundice recurrence Liver enzymes decreased remarkably, while there was a subsequent improvement in patient’s lipid profile EP Hyperlipidemia is one of the most common complications of cholestatic AC C liver disease Primary biliary cirrhosis (PBC) and similar disorders may be accompanied by marked hypercholesterolemia However, cholesterol levels in cholestatic liver diseases above 900 mg/dl are extremely rare in the literature with only few reports The range of serum cholesterol concentrations is wide, from 120mg/dl to 1775 mg/dl in one report of 284 patients, while the mean cholesterol level was 369.5 mg/dl8 The pathophysiology of dyslipidemia in cholestasis is not well established and is still under investigation The mechanism of ACCEPTED MANUSCRIPT hypercholesterolemia in cholestasis is different from that in other disorders as unusual lipoproteins are present In patients with cholestatic liver disease, the increase in serum cholesterol levels is largely due to an increased level of lipoprotein-X (LP-X) , an abnormal lipoprotein particle within the LDL density RI PT region that is rich in free cholesterol and phospholipids6 Although elevated levels of lipoprotein X has been associated with hyperviscosity syndrome9, the association between lipoprotein X and coronary heart diseases is unclear SC The available data suggest that, despite hypercholesterolemia , patients with PBC are not at increased risk of atherosclerosis6,8,10 LP-X has been shown M AN U to have anti-atherogenic properties as it inhibits the oxidation of normal LDL particles and prevents oxidized LDL from disrupting survival mechanisms in vascular endothelial cells11 Consequently, the increased cholesterol levels due to LP-X may actually reduce atherosclerotic risk TE D Most of studies for cholestatic liver diseases and hyperlipidemia are available for PBC The data for other specific types of cholestatic syndromes except for PBC is sparse in the literature The efficacy of drug therapy in EP lowering cardiovascular morbidity and mortality in PBC and cholestatic liver diseases is uncertain6 The administration of lipid-lowering agents (LLA) in AC C these syndromes is still controversial6,12 Further studies are required to be performed to estimate the lipid treatment in cholestatic disease In our case, we did not administrate LLA for two reasons Firstly, we thought that the hyperlipidemia in our patient was reversible by treating the primary cause of the cholestasis and also, we wanted to avoid a possible drug toxicity in this patient with impaired liver enzymes12 Moreover we disputed the necessity of ACCEPTED MANUSCRIPT treating the hyperlipidemia in cholestatic liver disease, as most of the studies have shown that these patients are not at high risk for CAD In conclusion, this was a rare case of a new-onset, rapid, and extreme hyperlipidemia due to cholestatic liver syndrome In such cases, treatment of RI PT the primary disorder is associated with normalization of the lipid levels The administrations of LLA should be personalized according to the physician’s and patient’s preferences AC C EP TE D M AN U SC Conflict of interest: none ACCEPTED MANUSCRIPT References RI PT Rallidis LS, Lekakis J PCSK9 inhibition as an emerging lipid lowering therapy: Unanswered questions Hellenic J Cardiol 2016;57:86-91 Hackam DG, Anand SS Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence Jama 2003;290:932-940 Andrikopoulos G, Terentes-Printzios D, Tzeis S, et al Epidemiological characteristics, management and early outcomes of acute coronary syndromes in Greece: The PHAETHON study Hellenic J Cardiol 2016;57:157-166 Phatlhane DV, Zemlin AE Severe hypercholesterolemia mediated by lipoprotein X in a patient with cholestasis Annals of hepatology 2015;14:924-928 Vodnala D, Rubenfire M, Brook RD Secondary Causes of Dyslipidemia Am J Cardiol 2012;110:823-825 Sorokin A, Brown JL, Thompson PD Primary biliary cirrhosis, hyperlipidemia, and atherosclerotic risk: a systematic review Atherosclerosis 2007;194:293-299 Jankowski K, Wyzgal A, Wierzbicka A, Tronina O, Durlik M, Pruszczyk P Rapid normalization of severe hypercholesterolemia mediated by lipoprotein X after liver transplantation in a patient with cholestasis - a case report Acta biochimica Polonica 2015;62:621-623 Crippin JS, Lindor KD, Jorgensen R, et al Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis: what is the risk? Hepatology 1992;15:858-862 Rosenson RS, Baker AL, Chow MJ, Hay RV Hyperviscosity syndrome in a hypercholesterolemic patient with primary biliary cirrhosis Gastroenterology 1990;98:1351-1357 Longo M, Crosignani A, Battezzati PM, et al Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis Gut 2002;51:265-269 Chang PY, Lu SC, Su TC, et al Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation Journal of lipid research 2004;45:2116-2122 Anfossi G, Massucco P, Bonomo K, Trovati M Prescription of statins to dyslipidemic patients affected by liver diseases: a subtle balance between risks and benefits Nutrition, Metabolism and Cardiovascular Diseases 2004;14:215-224 SC 10 11 AC C 12 EP TE D M AN U ACCEPTED MANUSCRIPT Table Patient’s blood tests January 2014: patient’s first hospitalization; March 2016: patient’s second hospitalization; April 2016: one month followup after his second hospitalization; May 2016: two months follow-up after his RI PT second hospitalization; June 2016: three months follow-up after his second hospitalization March April May June 2014 2016 2016 2016 2016 TC (mg/dl) 222 958 769 334 254 LDL-C (mg/dl) 172 871 671 215 161 HDL-C (mg/dl) 32 36 67 87 67 TG (mg/dl) 92 256 153 160 129 AST (U/l) 122 116 104 39 53 ALT (U/l) 61 82 79 54 44 685 1092 794 674 503 206 2587 1118 535 411 Bilirubin (mg/dl) 5.85 12.6 3.63 0.97 0.57 Direct bilirubin (mg/dl) 4.3 9.18 2.10 0.38 0.24 TE D M AN U SC January GGT (U/l) AC C EP ALP (U/l) TC: Total cholesterol; LDL-C: Low-density lipoprotein - Cholesterol; HDL-C: High-density lipoprotein - Cholesterol; TG: Triglycerides; AST: Aspartate transaminase; ALT: Alanine transaminase; transpeptidase; ALP: Alkaline phosphatase GGT: gamma-glutamyl ...ACCEPTED MANUSCRIPT Case Report New- onset severe hypercholesterolemia in a patient with cholestatic liver disease Should we treat the lipids? Panteleimon E Papakonstantinoua, Eirini Theodorakib,... sparse in the literature The efficacy of drug therapy in EP lowering cardiovascular morbidity and mortality in PBC and cholestatic liver diseases is uncertain6 The administration of lipid-lowering... muscle antibodies (ASMA) and anti-nuclear antibodies (ANA) were negative for primary biliary cirrhosis The patient M AN U underwent a new ERCP, removal of the ductal gallstones and new stenting