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

1. CONTROVERSE IN TERAPIA CU
STATINE LA PACIENTII CU
HEPATOPATII CRONICE DIFUZE
Andritoiu Alexandru, MD
Sp. Militar Craiova, Sectia Boli
Interne

2. Background
• In obstructive liver disease, there is marked
disease
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.

3. Dyslipidemia in Chronic Liver Disease
82.5%
N = 160 pts
15%
2.5%
CT scazut
CT normal
CT >
FATIMA MEHBOOB, F.A RANJHA
Department of Medicine, Sheikh Zayed Medical College, Rahim Yar Khan
Pakistan

4. Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver
Aminotransferase Levels: A Therapeutic Dilemma
• Statins and hepatotoxicity (!?!)
• Transaminitis-liver enzyme levels are elevated in the
Transaminitis
absence of proven hepatotoxicity.
• This class effect is usually asymptomatic, reversible, and
dose-related - often occurs in the first 12 weeks of
therapy
• Isolated cases of autoimmune hepatitis revealed by
statin treatment have been described with variable
degrees of severity (idiosyncratic or an immunoallergic
reaction)
• Statins were associated with fulminant 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
individual assessment of risks and benefits.
Calderon R et al. - Mayo Clin Proc. 2010: 85(4): 349–356.

5. Incidence of Increase in Serum ALT Levels >3 Times the ULN
Among Different Trials, by Statin Dose
ULN = upper limit normal

6. CITOLIZA HEPATICA INDUSA DE
STATINE
(TRANSAMINITA)
CAZ CLINIC

7. Caz clinic
T. 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)

8. Ex. biologice
Colesterol total 232 mg/dL
LDL Col 169 mg/dL
HDL Col 44 mg/dL
Lipide totale 709 mg/dL
Gama GT 334 UI/mL
TGP 104 UI/L
TGO 15 UI/L

9. Glicemie = 126 mg/dL

10. Ecografia hepatica
Ecostructura hepatica omogena
Litiaza biliara

11. FIBROMAX
NAFLD/NASH ???
F1 A3 S3 N0

12. Algorithm for management of abnormal
liver enzymes before and during statin
treatment. ULN = upper limit of normal
Calderon R et al. - Mayo Clin Proc. 2010: 85(4): 349–356.

13. Dyslipidemia in patients with nonalcoholic
fatty liver disease (NAFLD)

14. Dyslipidemia in patients with NAFLD
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

15. Caz clinic (NAFLD)
G. Gheorghe, 45 ani, Craiova
Gheorghe
DIAGNOSTIC
• Sdr. Metabolic
Obezitate abdominala gr. 2
HTA primara gr 1
Dislipidemie aterogena
Steatoza hepatica (cuzinet pseudotumoral)

16. Ecografia hepatica
Cuzinet in hilul hepatic
Ecogenitate hepatica crescuta

17. RMN
Exclude eventuala tumora hepatica

18. Analize biochimice

19. Fibromax
F1 A3 S3 N1

20. Statins 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
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
experience with atorvastatin in patients with NAFLD;
it is the only statin to date to show a reduced
cardiovascular morbidity in patients with NAFLD.

21. Hepatology - June 2012

22. Dislipidemia in
chronic hepatitis C

23. Caz clinic
• N. Elena, 59 ani
• Hepatita cr. VHC
•
•
•
•
TGO 57 UI/L
TGP 72 UI/L
Ag HBS abs
AC VHC ++

24. Stadializare histologica
PBH 05/03/2011
SCOR HAI =12
(9+3)
SCOR METAVIR
A2, F2, steatoza usoara
HEPATITA CRONICA MODERAT ACTIVA
Incarcatura virala 960.676 UI/ml
15/09/2010

25. Profilul lipidic
CT 273 mg/dL
LDL-Col 184.5 mg/dL
HDL-Col 64.5 mg/dL
TG 120 mg/dL
Lipide totale 824 mg/dL

26. FIBROMAX
F2 A2 S1 N1

27. How safe and useful are statins in
chronic hepatitis C?

28. Hepatology, 2007;46:1453-1463
Hepatology
N: 326 pts;NAFL: 64%;Hepatita cronica VHC: 23%
NAFL
VHC
Pravastatin 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.

29. Berlin, Germany, March 30-April 3, 2011
1964-2013
1964-2013
According to Eugen Georgescu, MD, PhD, of the Filantropia Municipal Hospital
Georgescu
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 cholesterollowing 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 %.
“Fluvastatin showed a significant improvement in terms of EVR and SVR in
chronic hepatitis C patients treated with standard PegIFN-ribavirin therapy,”
“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
presence of high cholesterol levels.”

30. ….recent advances have shown that statins play a
role in improving treatment outcome and increasing
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 interferon

32. Relationship between statin therapy, low-density lipoprotein levels, and sustained virologic response.

34. Hyperlipidemia in Chronic Cholestatic
Liver Disease

35. Hyperlipidemia in
Primary Biliary Cirrhosis
• Particular lipoprotein 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

36. Treatment
• 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
(1) Longo M et al. - Curr Treat Options Gastroenterol 2001;4:111-114
(2) Liberopoulos EN et al. – Open Cardiovasc Med J 2010;4:120-126

37. Caz clinic - colestaza
T. Victoria, 41 ani, Craiova
Victoria
• Neoplasm san stg. operat
• Metastaze hepatice si osoase
• Sdr. icteric

38. Ex. 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/L
F alk 1246 UI/L
•
•
•
•
•
Colesterol 242-230 mg/dL
LDL-Col 145 mg/dL
HDL-Col 15 mg/dL
TG 346 mg/dL
Lipide totale 953 mg/dL

39. Ecografia Abdominala
Metastaze hepatice
VB
Colecist cu sluge

40. Dislipidemia in Cirrhosis

41. Caz clinic
S. ANETA, F, 60 ani
• Afirma consumul cronic de alcool
DIAGNOSTIC
• Ciroza hepatica etanolica (Child-Pugh B)
• Hipercolesterolemie
• Diabet zaharat (cirogen)
• HTA primara grad. 2 RC inalt

42. Istoric
Martie 2006
• CH decompensata P/P-Colestaza
Iunie 2006
• confirmare H-P (laparoscopic-colecistectomie)
Ianuarie 2012
• DZ
Aprilie 2013
• HTA
• Repetate spitalizari
• NB. Testele virusologice negative
• Etiologie: ETANOLICA

43. Rezultat H-P

44. Ecografia abdominala
•
•
•
•
Ficat: cirotic - LD 14.5 CM, LS 7.5 CM
Ficat
V. porta: 16 mm, flux hepatopet-HTP
porta
Colecist: exclus chirurgical
Splina: ecogena 11/4.5 cm

45. Ex Biologice
NORMALE
• HLG
• Na, K, Ca, Mg
• Uree, creatinina
• Acid uric
• Ex. Sumar urina
•
•
•
•
•
•
•
•
PATOLOGICE
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

46. LIPIDOGRAMA
22-30.04.213
•
•
•
•
•
Colesterol total: 419-322 mg/dL
total
LDL-Col: 311-236 mg/dL
HDL-Col: 87-64 mg/dL
Non HDL-Col: 332-258 mg/dL
HDL-Col
TG: 104-111 mg/dL

47. CT mg/dL
Evolutia profilului Col. Total
450
400
350
300
250
200
150
100
50
0
febr. 2006
apr. 2006
febr. 2010
Data
ian. 2012
apr. 2013

48. TRATAMENT
•
•
•
•
•
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

49. Evolutia Colesterolului total
CT (mg/dL)
450
Sortis+Ezetrol
400
350
300
250
200
150
100
50
0
febr. 2006 apr. 2006 febr. 2010 ian. 2012
apr. 2013 aug. 2013

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

51. Caz clinic
C. Stefan, M, 63 ani, Craiova
DIAGNOSTIC
• Ciroza hepatica VHC + alcool (Child-Pugh A)
• HTA primara grad 3 cu RC inalt
• Cardiopatie hipertensiva
• Dislipidemie
• Disglicemie
• Obezitate gr 1

52. Ecografia abdominala
Ficat heterogen
Splenomegalie

53. Analize (15.03.2013)
Ag HBS abs; Ac VHC prezenti

54. FIBROMAX
F4 A2 S3 N1

55. 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

56. Analize control (08.05.2013)
Ac VHC >11 (VN <0.8-1)

57. Evolutia profilului lipidic
800
734
700
597
600
500
400
300
241
200
181
176
132
102
100
44
100
29
0
mg/dL
CT
LDL
HDL
martie 2013
TG
mai 2013
Lipide T

58. Caz clinic
N. FLOREA, 62 ani, mediul rural
• Ciroza hepatica etanolica (Child-Pugh A)

59. Echografia abdominala
• FICAT: macronodular, neomogen, ecogen difuz, LD 14.5
cm, LS 8 cm; fara procese localizate.
• Colecist: perete ecogen, septat, cu calculi multipli de
aprox. 1 cm fiecare
• CBP: calibru normal
• V. porta: moderat marita in hil (15 mm)-flux de HTPo
• Pancreas: hiperecogen, omogen-dimensiuni moderat
crescute
• Splina: omogena, ecogena 14/6.5 cm
• RD+ RS: dimensiuni, ecostructura normala
• Vezica urinara: perete suplu
• Prostata: omogena, ecogena,dimensiuni normale
• Fara ascita

61. Observatii personale
Dislipidemia in CH asociata:
asociata
• Consumului de alcool
• Diabetului (cirogen)

62. Statin Therapy
Decreases the Risk
of Hepatic
Decompensation in
Cirrhosis
Sonal Kumar, MD,
Kumar
Brigham and Women’s Hospital, New York
A small retrospective 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)

63. ,,We found less progression of liver
disease in patients taking statins, and a
lower mortality rate. This is contrary to
prior beliefs that statins may not be safe in
patients with cirrhosis; in fact, they may be
beneficial,,

64. 70.4%
29.6%
Child A
Child B/C
N = 243 pts (82 pts CH + statins;162 controls CH-non statins)
Follow-up: 36 Mo
Primary outcome: hepatic decompensation

65. Rata decompensarilor hepatice
55.6%
39.5%
CH statins
Control
The use of a statin was associated with a 56% reduction in risk for hepatic
decompensation
(95% confidence interval [CI], 0.27 to 0.71)

66. Rata aparitiei ascitei
37%
20.9%
CH statins
Control

67. Rata mortalitatii
50.6%
37%
CH statins
Control
Statin use was significantly associated with a 51% reduction in mortality
(95% CI, 0.29 to 0.81),

68. Efectul protector al statinelor in CH
IPOTEZE:
• Efecte hemodinamice
- statinele reduc HTPortala
- amelioreaza disfunctia endoteliala de la
nivelul sinusoidelor hepatice
• Efecte moleculare benefice
- creste NO (vasodilatator periferic)

69. Message Take Home
Statin therapy in Liver Disease?

70. FDA Expands Advice on Statin
Risks (2012)
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.