Controverse in terapia cu statine in hepatopatiile cronice difuze

CONTROVERSE IN CONTROVERSE IN TERAPIA CU STATINE TERAPIA CU STATINE

LA PACIENTII CU LA PACIENTII CU HEPATOPATII HEPATOPATII

CRONICE DIFUZECRONICE DIFUZEAndritoiu Alexandru, MDAndritoiu Alexandru, MD

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

Glicemie = 126 mg/dL

Ecografia hepaticaEcografia hepatica

Ecostructura Ecostructura hepatica omogenahepatica omogena

Litiaza biliaraLitiaza biliara

FIBROMAXFIBROMAX

F1 A3 S3 N0

NAFLD/NASH ???NAFLD/NASH ???

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)

Ecografia hepaticaEcografia hepatica

Cuzinet in hilul hepaticCuzinet in hilul hepatic

Ecogenitate hepatica crescutaEcogenitate hepatica crescuta

RMNRMN

Exclude eventuala tumora hepaticaExclude eventuala tumora hepatica

AnalizeAnalize biochimicebiochimice

FibromaxFibromax

F1 A3 S3 N1

Statins in NAFLStatins in NAFL

• 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

Caz clinicCaz clinic

• N. Elena,N. Elena, 59 ani• Hepatita cr. VHCHepatita cr. VHC

• TGO 57 UI/LTGO 57 UI/L• TGP 72 UI/LTGP 72 UI/L• Ag HBS abs• AC VHC ++AC VHC ++

Stadializare histologicaStadializare histologicaPBH 05/03/2011

SCOR HAISCOR HAI =12

(9+3)

SCOR METAVIRSCOR METAVIR

A2, F2, steatoza usoara

HEPATITA CRONICA MODERAT ACTIVAHEPATITA CRONICA MODERAT ACTIVA

Incarcatura virala 960.676 UI/ml Incarcatura virala 960.676 UI/ml 15/09/201015/09/2010

Profilul lipidicProfilul lipidic

CT 273 mg/dLCT 273 mg/dLLDL-Col 184.5 mg/dLLDL-Col 184.5 mg/dLHDL-Col 64.5 mg/dLHDL-Col 64.5 mg/dLTG 120 mg/dLTG 120 mg/dLLipide totale 824 mg/dLLipide totale 824 mg/dL

FIBROMAXFIBROMAX

F2 A2 S1 N1

How safe and useful How safe and useful are statins in are statins in

chronic hepatitis C?chronic hepatitis C?

HepatologyHepatology, 2007;46:1453-1463

NN: 326 pts;NAFLNAFL: 64%;Hepatita cronica VHCHepatita cronica VHC: 23%Pravastatin 80 mg/ziPravastatin 80 mg/zi

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

• Particular lipoprotein patternlipoprotein pattern

• 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

Caz clinicCaz clinic - colestaza - colestaza

T. VictoriaT. Victoria, 41 ani, Craiova

• Neoplasm san stg. operat

• Metastaze hepatice si osoase

• Sdr. icteric

Ex. biologiceEx. biologice

• VSH 55 m/h• Hb 9.3 g/dL• Ht 27 %• Tb 57.000/mmc• TGO 955-285 UI/L• TGP 493-106 UI/L• BRT 10.9-9.5 mg/dL• CRP 12 mg/dL• GGT 1134 UI/LGGT 1134 UI/L• F alk 1246 UI/LF alk 1246 UI/L

• Colesterol 242-230 mg/dLColesterol 242-230 mg/dL• LDL-Col 145 mg/dLLDL-Col 145 mg/dL• HDL-Col 15 mg/dLHDL-Col 15 mg/dL• TG 346 mg/dLTG 346 mg/dL• Lipide totale 953 mg/dLLipide totale 953 mg/dL

Ecografia AbdominalaEcografia Abdominala

VB

Metastaze hepatice

Colecist cu sluge

Dislipidemia in Dislipidemia in CirrhosisCirrhosis

Caz clinic Caz clinic

S. ANETA, F, 60 aniS. ANETA, F, 60 ani

• Afirma consumul cronic de alcool

DIAGNOSTICDIAGNOSTIC

• Ciroza hepatica etanolica (Child-Pugh B)

• Hipercolesterolemie

• Diabet zaharat (cirogen)

• HTA primara grad. 2 RC inalt

IstoricIstoric Martie 2006 • CH decompensata P/P-ColestazaIunie 2006 • confirmare H-P (laparoscopic-colecistectomie)Ianuarie 2012 • DZ Aprilie 2013 • HTA

• Repetate spitalizari• NB. Testele virusologice negative• Etiologie: ETANOLICA

Rezultat H-PRezultat H-P

Ecografia abdominalaEcografia abdominala

• FicatFicat: cirotic - LD 14.5 CM, LS 7.5 CM

• V. portaV. porta: 16 mm, flux hepatopet-HTP

• Colecist: exclus chirurgical

• Splina:Splina: ecogena 11/4.5 cm

Ex BiologiceEx Biologice

NORMALENORMALE• HLG• Na, K, Ca, Mg• Uree, creatinina• Acid uric• Ex. Sumar urina

PATOLOGICEPATOLOGICE• VSH 46 mm/h• Tb 76-98.000/mmc• TQ 15 sec, AP 90%• TGO (AST) 56-56 UI/L• TGP (ALT) 43-54 UI/L• BRT 1.7-1.4 mg/dL• GGT 431 UI/L• Glicemie 164 mg/dL

LIPIDOGRAMALIPIDOGRAMA22-30.04.21322-30.04.213

• Colesterol totalColesterol total: 419-322 mg/dL

• LDL-Col:LDL-Col: 311-236 mg/dL

• HDL-Col: HDL-Col: 87-64 mg/dL

• Non HDL-ColNon HDL-Col: 332-258 mg/dL

• TG:TG: 104-111 mg/dL

Evolutia profilului Col. Total

050

100150200250300350400450

febr. 2006 apr. 2006 febr. 2010 ian. 2012 apr. 2013

Data

CT

mg

/dL

TRATAMENTTRATAMENT

• Arginina 1000 mg/zi p.o.

• Liv 52 DS 2x1 cp/zi

• Norvasc 5 mg/zi

• Carvedilol 12.5 mg/zi

• Sortis 10 mg/zi + Ezetrol 10 mg/zi

Evolutia Colesterolului totalEvolutia Colesterolului total

0

50

100

150

200

250

300

350

400

450

febr. 2006 apr. 2006 febr. 2010 ian. 2012 apr. 2013 aug. 2013

CT (mg/dL) Sortis+EzetrolSortis+Ezetrol

Colesterol Total =211 mg/dL LDL Colesterol =151 mg/dL

Caz clinicCaz clinic

C. Stefan, M, 63 ani, C. Stefan, M, 63 ani, Craiova

DIAGNOSTICDIAGNOSTIC• Ciroza hepatica VHC + alcool (Child-Pugh A)Ciroza hepatica VHC + alcool (Child-Pugh A)• HTA primara grad 3 cu RC inalt• Cardiopatie hipertensiva• Dislipidemie• Disglicemie • Obezitate gr 1

Ecografia abdominalaEcografia abdominala

Ficat heterogenFicat heterogen

SplenomegalieSplenomegalie

Analize (15.03.2013)

Ag HBS abs; Ac VHC prezenti

F4 A2 S3 N1

FIBROMAXFIBROMAX

Tratament

• Perindopril 8 mg/zi

• Carvedilol 6.25 mg/zi

• Silimarina 2 x 1 cp/zi

• LIV 52 DS 2x1 cp/zi

• L-Arginina 1g/zi

• Sortis 20 mg/zi

Analize control (08.05.2013)

Ac VHC >11 (VN <0.8-1)

Evolutia profilului lipidicEvolutia profilului lipidic

241

176

44

102

734

181

132

29

100

597

0

100

200

300

400

500

600

700

800

CT LDL HDL TG Lipide T

martie 2013 mai 2013

mg/dL

Caz clinicCaz clinic

N. FLOREA, 62 ani, mediul rural

• Ciroza hepatica etanolica (Child-Pugh A)

Echografia abdominalaEchografia abdominala

• 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

crescute• Splina:Splina: omogena, ecogena 14/6.5 cm omogena, ecogena 14/6.5 cm• RD+ RS: dimensiuni, ecostructura normala • Vezica urinara: perete suplu• Prostata: omogena, ecogena,dimensiuni normale• Fara ascita

Observatii personaleObservatii personale

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,,

N = 243 pts (82 pts CH + statins;162 controls CH-non statins)

Follow-up: 36 Mo

Primary outcome: hepatic decompensation

29.6%

70.4%

Child A Child B/C

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.

FDA Expands Advice on Statin Risks (2012)