CONTROVERSE IN CONTROVERSE IN TERAPIA CU STATINE TERAPIA CU STATINE LA PACIENTII CU LA PACIENTII CU HEPATOPATII CRONICE HEPATOPATII CRONICE DIFUZE DIFUZE Andritoiu Alexandru, MD Andritoiu Alexandru, MD Sp. Militar Craiova, Sectia Sp. Militar Craiova, Sectia Boli Interne Boli Interne
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Controverse in terapia cu statine in hepatopatiile cronice difuze
sunt prezentate rezultate din studii si cazuri clinice particulare, exemplificand-se dislipidemia din diverse afectiuni hepatice difuze si rolul terapiei cu statine, intre riscuri si beneficii la acesti pacienti
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CONTROVERSE IN CONTROVERSE IN TERAPIA CU STATINE TERAPIA CU STATINE
LA PACIENTII CU LA PACIENTII CU HEPATOPATII HEPATOPATII
Sp. Militar Craiova, Sectia Boli Sp. Militar Craiova, Sectia Boli InterneInterne
BackgroundBackground
• In obstructive liver diseaseobstructive liver disease, there is marked elevation of free cholesterol and phospholipids
• In acute hepatocellular disease such as alcoholic or viral hepatitis, there is a cholestatic phase and similar changes may be seen (e.g. increased cholesterol and phospholipid levels).
• In chronic liver disease due to decreased biosynthetic capacity of liver, low levels of cholesterol and triglycerides are found.
Dyslipidemia in Chronic Liver Disease
2.5%
82.5%
15%
CT scazut CT normal CT >
N = 160 pts
FATIMA MEHBOOB, F.A RANJHADepartment of Medicine, Sheikh Zayed Medical College, Rahim Yar Khan
Pakistan
Statins in the Treatment of Dyslipidemia in Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver the Presence of Elevated Liver
Aminotransferase Levels: A Therapeutic Aminotransferase Levels: A Therapeutic DilemmaDilemma
• Statins and hepatotoxicity (!?!)• TransaminitisTransaminitis-liver enzyme levels are elevated in the
absence of proven hepatotoxicity. • This class effectclass effect is usually asymptomatic, reversible, and asymptomatic, reversible, and
dose-related -dose-related - often occurs in the first 12 weeksfirst 12 weeks of therapy
• Isolated cases of autoimmune hepatitisautoimmune hepatitis revealed by statin treatment have been described with variable degrees of severity (idiosyncratic or an immunoallergic reaction)
• Statins were associated with fulminant liver failurefulminant liver failure in 3 of 51,741 cases of liver transplants in the United States from 1990 to 2002.For each patient, the decision should be based on an For each patient, the decision should be based on an
individual assessment of risks and benefits.individual assessment of risks and benefits.
Calderon R et al. - Mayo Clin Proc. 2010: 85(4): 349–356.
Incidence of Increase in Serum ALT Incidence of Increase in Serum ALT Levels >3 Times the ULN Among Levels >3 Times the ULN Among Different Trials, by Statin DoseDifferent Trials, by Statin Dose
ULN = upper limit normal
CITOLIZA HEPATICA CITOLIZA HEPATICA INDUSA DE STATINE INDUSA DE STATINE
(TRANSAMINITA)(TRANSAMINITA)CAZ CLINICCAZ CLINIC
Caz clinic Caz clinic
T. ADRIANA, 46aniT. ADRIANA, 46ani• Istoric de dislipidemie mixta• Diabet zaharat tip 2-echilibrat
• Descoperita la un control biologic cu citoliza hepatica• Se interneaza ptr investigatii suplimentare (in obs. Hepatita cr. virala)• Neaga consumul de alcool
Tratament:ADO + Statina
(Atorvastatin 20-80 mg/zi sau Crestor 20 mg/zi de peste 2 ani)
Ex. biologiceEx. biologice
Colesterol total 232232 mg/dLLDL Col 169 169 mg/dLHDL Col 44 mg/dLLipide totale 709 709 mg/dLGama GTGama GT 334334 UI/mL UI/mLTGP 104 UI/LTGP 104 UI/LTGO 15 UI/L
Algorithm for management of abnormal Algorithm for management of abnormal liver enzymes before and during statin liver enzymes before and during statin treatment.treatment. ULN = upper limit of normal
Calderon R et al. - Mayo Clin Proc. 2010: 85(4): 349–356.
Dyslipidemia in patients Dyslipidemia in patients with nonalcoholic fatty with nonalcoholic fatty liver disease (NAFLD)liver disease (NAFLD)
Dyslipidemia in patients with Dyslipidemia in patients with NAFLDNAFLD
The dyslipidemia in NAFLD is characterized by:• increased serum triglycerides, • increased small, dense LDL particles, and low
HDL) cholesterol.
• The pathogenesis of dyslipidemia in NAFLD is not well understood, but it is likely related to hepatic overproduction of the very low-density lipoprotein (VLDL) particles and dysregulated clearance of lipoproteins from the circulation
Chatrath H et al. – Semin Liver Dis 2012;32:22-29
Caz clinic (NAFLD)Caz clinic (NAFLD)
G. GheorgheG. Gheorghe, 45 ani, Craiova
DIAGNOSTICDIAGNOSTIC
• Sdr. MetabolicSdr. MetabolicObezitate abdominala gr. 2HTA primara gr 1Dislipidemie aterogenaSteatoza hepatica (cuzinet pseudotumoral)
• There is unequivocal evidence that cardiovascular disease is the most common cause of mortality in patients with NAFLD.
• Aggressive treatment of dyslipidemia plays a critical role Aggressive treatment of dyslipidemia plays a critical role in the overall management of patients with NAFLD. in the overall management of patients with NAFLD.
• Statins are the first-line agents to treat high cholesterol and their dosage should be adjusted based on achieving therapeutic targets and tolerability.
• Although all statins appear to be effective in improving cholesterol levels in patients with NAFLD, there is more is more experience with atorvastatin in patients with NAFLD;experience with atorvastatin in patients with NAFLD; it is the only statin to date to show a reduced it is the only statin to date to show a reduced cardiovascular morbidity in patients with NAFLD. cardiovascular morbidity in patients with NAFLD.
Hepatology -Hepatology - June 2012
Dislipidemia in Dislipidemia in chronic hepatitis Cchronic hepatitis C
Conclusion: High-dose pravastatin (80mg/day) administered to hypercholesterolemic subjects with chronic liver disease significantly lowered LDL-C, TC, and TGs in comparison with the placebo and was safe and well tolerated.
Berlin, Germany, March 30-April Berlin, Germany, March 30-April 3, 20113, 2011
According to Eugen GeorgescuEugen Georgescu, MD, PhD, of the Filantropia Municipal Hospital in Craiova, Romania, and his colleagues, people living with hepatitis C virus (HCV) had improved sustained virologic responses (SVRs, or viral cures) when treated with pegylated interferon and ribavirin (IFN/RBV) plus the cholesterol-pegylated interferon and ribavirin (IFN/RBV) plus the cholesterol-lowing statin fluvastatin (Lescol).lowing statin fluvastatin (Lescol).
According to a statistical analysis known as an odds ratio, the chance of achieving an SVR using all three drugs was nearly doubled.
SVRs were also more common among those receiving IFN/RBV plus Lescol: 62% vs. 50 %.62% vs. 50 %.
““Fluvastatin showed a significant improvement in terms of EVR and SVR in Fluvastatin showed a significant improvement in terms of EVR and SVR in chronic hepatitis C patients treated with standard PegIFN-ribavirin therapy,” chronic hepatitis C patients treated with standard PegIFN-ribavirin therapy,” ““This synergistic effect with interferon…suggests that lipid-lowering agents might This synergistic effect with interferon…suggests that lipid-lowering agents might favor HCV clearance and can be useful in hep C treatment, irrespective of the favor HCV clearance and can be useful in hep C treatment, irrespective of the presence of high cholesterol levels.”presence of high cholesterol levels.”
1964-20131964-2013
….recent advances have shown that statins play a statins play a role in improving treatment outcome and increasing role in improving treatment outcome and increasing the quality of life of HCV patients;the quality of life of HCV patients; however, the exact mechanism underlying their role is yet to be determined.
inhibition of HCV replication when used in combination with interferoninhibition of HCV replication when used in combination with interferon
Relationship between statin therapy, low-density lipoprotein levels, and sustained virologic response.
Hyperlipidemia in Hyperlipidemia in Chronic Cholestatic Liver Chronic Cholestatic Liver
DiseaseDisease
Hyperlipidemia in Hyperlipidemia in Primary Biliary CirrhosisPrimary Biliary Cirrhosis
• Hyperlipidemia with a marked increase of LDL and HDL cholesterol levels is a common feature in patients with chronic cholestatic liver disease
Longo M et al. - Curr Treat Options Gastroenterol 2001;4:111-114
TreatmentTreatment
• Ursodeoxycholic acid (UDCA)• Cholestyramine • Administration of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG CoA) reductase inhibitors should be limited to hypercholesterolemic patients with mild chronic cholestatic liver diseases (low HDL Cholesterol)1
• Fenofibrate + UDCA2
(2) Liberopoulos EN et al. – Open Cardiovasc Med J 2010;4:120-126
(1) Longo M et al. - Curr Treat Options Gastroenterol 2001;4:111-114
• FICATFICAT: macronodular, neomogen, ecogen difuz, LD 14.5 : macronodular, neomogen, ecogen difuz, LD 14.5 cm, LS 8 cm; fara procese localizate.cm, LS 8 cm; fara procese localizate.
• Colecist: perete ecogen, septat, cu calculi multipli de aprox. 1 cm fiecare
• CBP: calibru normal• V. portaV. porta: moderat marita in hil (15 mm)-flux de HTPo: moderat marita in hil (15 mm)-flux de HTPo• Pancreas: hiperecogen, omogen-dimensiuni moderat
Dislipidemia in CH asociataDislipidemia in CH asociata:• Consumului de alcool• Diabetului (cirogen)
Statin Therapy Statin Therapy Decreases the Risk Decreases the Risk
of Hepatic of Hepatic Decompensation in Decompensation in
CirrhosisCirrhosis Sonal KumarSonal Kumar, MD,
Brigham and Women’s Hospital, New York
A small retrospective studyretrospective study found that patients with cirrhosis who took statins were
less likely to develop hepatic decompensation or die compared with matched patients who
were not on statins.
presented at Digestive Disease Week SAN DIEGO (May 21, 2012)
,,We found less progression of liver We found less progression of liver disease in patients taking statins, and a disease in patients taking statins, and a lower mortality rate. This is contrary to lower mortality rate. This is contrary to prior beliefs that statins may not be safe in prior beliefs that statins may not be safe in patients with cirrhosis; in fact, they may be patients with cirrhosis; in fact, they may be beneficial,, beneficial,,
Rata decompensarilor Rata decompensarilor hepaticehepatice
55.6%
39.5%
CH statins Control
The use of a statin was associated with a 56% reduction in risk for hepatic The use of a statin was associated with a 56% reduction in risk for hepatic decompensationdecompensation
(95% confidence interval [CI], 0.27 to 0.71)
Rata aparitiei asciteiRata aparitiei ascitei
20.9%
37%
CH statins Control
Rata mortalitatiiRata mortalitatii
50.6%
37%
CH statins Control
Statin use was significantly associated with a 51% reduction in mortalityStatin use was significantly associated with a 51% reduction in mortality (95% CI, 0.29 to 0.81),
Efectul protector al statinelor in CHEfectul protector al statinelor in CH
IPOTEZE:IPOTEZE:
•Efecte hemodinamiceEfecte hemodinamice
- statinele reduc HTPortala
- amelioreaza disfunctia endoteliala de la nivelul sinusoidelor hepatice
•Efecte moleculare beneficeEfecte moleculare benefice - creste NO (vasodilatator periferic)
Message Take HomeMessage Take Home
Statin therapy in Liver Disease?Statin therapy in Liver Disease?
Routine monitoring of liver enzymes in the blood, once considered standard procedure for statin users, is no longer needed.
Such monitoring has not been found to be effective in predicting or preventing the rare occurrences of serious liver injury associated with statin use.