Diabetes and chronic liver disease (CLD) commonly coexist and interact with each other. CLD can cause abnormalities in glucose metabolism, while diabetes accelerates progression of CLD. For compensated CLD, anti-diabetic treatment is similar to those without liver disease. In decompensated CLD, tight glycemic control is not the goal and insulin therapy requires careful monitoring to avoid hypoglycemia due to altered liver function and insulin metabolism.

1. Prof. Ashraf Talaat ,MD.
Internal Medicine Departement
Endocrinology,Diabetes&Metabolism Unit
Chief of Nephrology&Renal Dialysis Units
Banha Faculty of Medicine
Banha University
Egypt
Diabetes & The Liver
from old concepts to new evidence
UEDA,2016 ,Aswan

2. “ DDA”
Delta Diabetes Association

3. Pharos civilization in Ancient Egypt … on The
Nile River...made the first lesson to the whole
world …which is….!!!???

5. 2/17/2016

6. Agenda
 Magnitude of the problem.
 Effect of CLD on diabetes.
 Effect of diabetes on CLD.
 Anti-diabetic agents and the normal liver.
 Management of hyperglycemia in CLD:
o In patients with compensated CLD.
o In patients with decompensated CLD.

7. Agenda
 Magnitude of the problem.

8. Prevalence of diabetes in adults
(20-79 years)
 387 million people have diabetes in the world and more
than 37 million people in the Middle East and North Africa
(MENA)Region, by 2035 this will rise to 68 million.
 The Middle East and North Africa (MENA)Region,
1 in 10 adults have diabetes; the Region has the highest
prevalence of diabetes.
 in Egypt in 2014 , There were over 7.5 million cases of
diabetes
International Diabetes Federation. IDF Diabetes Atlas, 6th edition. Brussels.

9. The rates of diabetes in Egypt has significantly
increased exceeding international rates, (IDF
,2016).
Egypt is now ranked eighth highest in the world
in terms of the disease.

10.  Diabetes and CLD are common
conditions in Egypt.
 The 2 conditions often coexist.
DM CLD
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

11. Agenda
 Magnitude of the problem.
 Effect of CLD on diabetes.

12. Fix the Defect

13. Diabetes & Liver diseases
Both problems have an important interaction
considering etiology & the presence of any
problem of each affect the management of the
other.

14. Liver is the main organ concerned with glucose
homeostasis through:
1)Glycogenesis :
In the postprandial state (under effect of insulin)
2) Glycogenolysis & Gluconeogenesis :
In the fasting state (mainly under effect of glucagon)

15. ??????????
What is the relationship
between liver diseases &
abnormalities of glucose
homeostasis
???????

16. Classified into 3 cateogries:
Liver diseases as a consequence of IR/ DM
Abnormalities of glucose metabolism as a
consequence of liver diseases
Diseases causes liver diseases & abnormalities of
glucose metabolism

17. Facing the
Problem..

18. 0 20 40 60
NASH
hronic active hepatitis
50 %
33 %
30 %Cirrhosis 60 %
Prevalence of diabetes

19. DM CLD
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.
NAFLD
Insulin
Resistance
HCV
Cirrhosis
Hepatogenous
diabetes ?!!

27. Abnormalities of glucose metabolism as a
consequence of liver diseases :
I) Hypoglycemia : Is rare in liver diseases, however it may occur in:
-Acute liver cell failure and terminal cirrhosis
-Hepatocellular carcinoma
II) Impaired glucose tolerance & DM:
-Hepatogenous DM
-Post-Liver Transplantation
-HCC

28. Hepatogenous DM
(Association of cirrhosis with impaired glucose metabolism)
 60% of cirrhotic patients have IGT
 20% of cirrhotic patients have DM
This is different from T2DM because it occurs in absence of risk factors e.g. age,
BMI or family history.
The mechanism underlying hepatogenous DM is:
“ insulin resistance”,
may be due to:
1. Hyperinsulinemia
2. Elevated level of FFA.
3. Chronic inflammation (through effect of inflammatory cytokines e.g. IL1,IL6 and
TNF-alpha).

29. Diseases causes liver diseases & abnormalities of
glucose metabolism
Metabolic diseases causing hypoglycemia
 Glycogen storage (type I, III).
 Hereditary fructose intolerance
 Tyrosinemia
Diseases causing DM
 Hemochromatosis
 Chronic hepatitis C
 Autoimmune liver diseases
 Cystic Fibrosis

30. Mechanisms of IGT/DM in CHC infection
A) Insulin Resistance .
B) Defective Insulin Secrection:
-Direct autoimmune damage of B-cells by the virus.
- Interferon
The incidence of new onset DM in CHC patients who achieved
SVR after IFN therapy is lower than the incidence in who failed
therapy.

31. Adverse impact of IR/T2DM on outcome in CHC
Natural History:
The association between IR/T2DM and CHC leads to more progression to liver
cirrhosis.
Response to therapy:
IR/T2DM patients are associated with reduced rates of RVR as well as SVR in CHC
treated patients.
Improvement of insulin sensitivity by life style modification and drugs
(metformin OR TZD) has improved the responsiveness of standard
antiviral therapy in non-diabetic patients especially in genotype 4 .
.

32. Be Positive…..always..!!!!!!!

33. Agenda
 Magnitude of the problem.
 Effect of CLD on diabetes.
 Effect of diabetes on CLD.
 Anti-diabetic agents and the normal liver.
 Management of hyperglycemia in CLD:
o In patients with compensated CLD.
o In patients with decompensated CLD.

34. Khan et al. Postgrad Med. 2012 Jul;124:130-7.
↑ fibrogenesis
& progression
to cirrhosis
↑ risk of liver failure
↑ risk of HCC
↑ premature mortality.↓ response to
antiviral ₨
CLD

35. Agenda
 Magnitude of the problem.
 Effect of CLD on diabetes.
 Effect of diabetes on CLD.
 Anti-diabetic agents and the normal liver.
 Management of hyperglycemia in CLD:
o In patients with compensated CLD.
o In patients with decompensated CLD.

36. Kindly think

37. When start, start
right

38. Agent
Hepatic
metabolism
Risk of
hepatotoxicity
Metformin
2nd generation SUs
Repaglinide
Pioglitazone
Acarbose
NO
YES
NO
NO
YES
YES
LOW
LOW
NO
LOW

39. Agent
Hepatic
metabolism
Risk of
hepatotoxicity
Sitagliptin
Saxagliptin
Vildagliptin
NO
YES
NO
YES LOW
NO

40.  Insulin:
 Insulin is metabolized by insulinase in
the liver and kidney.
 About 50% of insulin is removed, by
‘first-pass’ hepatic extraction.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

41. Statins:
 May cause elevation in liver enzymes:
o Minor: rarely exceeds 3 times ULN.
o Transient without long-term effects.
o Severe liver damage is very rare.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

42. Agenda
 Magnitude of the problem.
 Effect of CLD on Diabetes.
 Effect of diabetes on CLD.
 Anti-diabetic agents and the normal liver.
 Management of diabetes in CLD:
o In patients with compensated CLD.
o In patients with decompensated CLD.

43. Management of DM in Liver diseases
 It depends on:
1)Severity of liver disease:
Assessed by
 Child-Pugh Classification
 Model for End-stage Liver Disease (MELD)
2) Activity of liver disease:
 Assessed by the liver of transaminases (markers of liver cell injury).
The injury is considered significant if the level of ALT is 2.5 fold than normal.
3)Type and cause of diabetes.
4)Other factors :
e.g. age of patient, severity of diabetes, occupation, socioeconomic state,
presence of other diabetic complications

44.  Glycemic target:
Individualized
Moscatiello et al. Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 63-70
Compensated CLD
with good life expectancy
Decompensated CLD
with poor life expectancy
More aggressive target Non-aggressive target

45.  What are the signs of decompensation?
 Ascites.
 Coagulopathy.
 Encephalopathy.
Moscatiello et al. Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 63-70

46. Agenda
 Magnitude of the problem.
 Effect of CLD on diabetes.
 Effect of diabetes on CLD.
 Anti-diabetic agents and the normal liver.
 Management of diabetes in CLD:
o In patients with compensated CLD.
o In patients with decompensated CLD.

47. In patients with compensated CLD:
 Lifestyle modification:
 Mediterranean diet:
o High complex CHO.
o High monounsaturated fats.
o Low amounts of red meat.
 Weight loss: in patients with NAFLD.

48. In patients with compensated CLD:
 Pharmacologic therapy:
 The same as that without CLD … Why?
o Drug metabolism is altered (only
altered in patients with liver failure).
at higher risk for hepatotoxicity.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

49. In patients with compensated CLD:
 Metformin:
 First-line therapy in most patients.
 Stop:
o If liver or renal functions deteriorated.
o In the setting of acute illness.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

50.  Can we use metformin in
compensated patients with HCV?
Nkontchou et al. J Clin Endocrinol Metab, August 2011, 96(8):2601–2608
?Conclusions: use of metformin was associated
with reduced incidence of HCC & mortality.
In another study adding metformin to
interferon & ribavirin was associated with a
better response to anti-viral therapy.

51.  Can we use metformin in
compensated patients with NAFLD?
 Yes.
 It is safe and may be even beneficial.
Romero-Gómez et al. Hepatology 2009; 50: 1702-1708.

52. In patients with compensated CLD:
 Sulfonylureas:
 Safe to use.
 The main side effect is hypoglycemia.
 SUs with a short half-life such as glipizide
are preferred.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

53. In patients with compensated CLD:
 Repaglinide:
 Safe to use.
 Less hypoglycemia than SUs.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

54. In patients with compensated CLD:
 Pioglitazone:
 In patients with NAFLD may lead to
improvement in ALT and liver histology.
 Do Not use if ALT ≥ 3 times ULN.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

55. In patients with compensated CLD:
 DPP-4 inhibitors:
 Sitagliptin & saxagliptin can be safely
used without dose adjustment.
 Vildagliptin is not approved in patients
with hepatic insufficiency.
Khan et al. Postgrad Med. 2012 Jul;124:130-7.

56. Sodium-glucose transporter 2
inhibitors (sglt2i)
(GLIFLOZINS)

57. Sglt2 i
• Sodium-glucose co-transporter 2 (SGLT2)
• inhibitors work by blocking the reabsorption
of filtered glucose in the kidneys.
.This leads to glucosuria and improved
glycemic control.

58. Sodium-glucose co-transporter 2 (SGLT2) inhibitors
 Clinical trials showed an in incidence of liver damage and
breast and bladder cancers amongst those taking the drug but
not to a high enough degree to indicate a clear increase in risk.
 Sodium/glucose co-transporter 2 inhibitors as highly suitable
for the inhibition of progression of non-alcoholic fatty liver
disease (NAFLD), non-alcoholic steatohepatitis (NASH),
alcoholic fatty liver disease, diabetic fatty liver .

61. In patients with compensated CLD:
 Insulin:
 Higher doses may be needed due to
insulin resistance.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

62. In patients with compensated CLD:
 Statins:
 Safe in patients with compensated CLD.
 Especially helpful in patients with NAFLD.
 May be hepato-protective in patients
with HCV.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

63. In patients with compensated CLD:
Aspirin:
 Safe to use.
 The cardio-protective dose (75-150 mg)
is not Hepatotoxic.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

64. Agenda
 Magnitude of the problem.
 Effect of CLD on diabetes.
 Effect of diabetes on CLD.
 Anti-diabetic agents and the normal liver.
 Management of hyperglycemia in CLD:
o In patients with compensated CLD.
o In patients with decompensated CLD.

65.  Glycemic target in decompensated CLD:
 The objective is just to ↓ the osmotic
symptoms related to diabetes .. Why?
• Prognosis depends on the complications
of the primary hepatic disease, rather
than diabetes complications.
Moscatiello et al. Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 63-70

66. In patients with decompensated CLD:
 Lifestyle modification:
 >50% of patients are malnourished.
 Avoid dietary restriction as it may result in:
o Hypo-albuminemia.
o Coagulopathy due to ↓ vitamin K intake.
o Worsen overall prognosis.

67. In patients with decompensated CLD:
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.
Metformin
SU & Repaglinide
Pioglitazone
DPP-4 inhibitors
Aspirin & statins
Fear of lactic acidosis
Fear of hypoglycemia
Fear of hepatotoxicity
Limited experience
No prognostic benefit

68. Insulin

69. In patients with decompensated CLD:
 Insulin:
 The safest and most effective therapy.
 The main risk is severe hypoglycemia.
 Careful glucose monitoring is needed.
 Dose may be decreased due to reduced
hepatic breakdown of insulin.
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.

70. In patients with decompensated CLD:
Insulin Regimen
Meal-related insulin administration
00.00 08.00 12.00 18.00 24.00
Regular
Lispro
Aspart
Glulisine

71.  Why we don’t usually need basal insulin
in patients with decompensated CLD?
Tolman et al. Diabetes Care. 2007 Mar;30:734-43.
 Glycemic profile is characterized by
low fasting plasma glucose due to
↓ hepatic glucose production.

72. In patients with decompensated CLD:
 Follow up of glycemic control:
o SMBG is preferred over HbA1c …. WHY?
 Cirrhosis (± hypersplenism) reduces
RCSs life-span  false low HbA1c.

73. Summary
 Type 2 diabetes is associated with a large number of liver
disorders including elevated liver enzymes, fatty liver
disease, cirrhosis, hepatocellular carcinoma. In addition,
there is an unexplained association with HCV.
 The presence of liver disease (unless decompensated) has
little implication for the specific treatment of diabetes, and
the presence of diabetes has little implication for the specific
treatment of liver disease.
 Patients with decompensated liver disease are more
susceptible to hypoglycemia and require careful monitoring.
 There continues to be a need for long-term placebo
controlled trials for the treatment of NAFLD and for the
treatment of diabetes in patients with liver disease.

74. CONCLUSIONS

75. Compensated
CLD
Decompensated
CLD
Glycemic
target
Follow up
Lifestyle
modification
More aggressive Non aggressive
Dietary
modification
Avoid dietary
restriction
HbA1C SMBG

76. Metformin
SU & Repaglinide
Pioglitazone
DPP-4 inhibitors
Insulin
In patients with compensated CLD
Stop if liver or renal
function deteriorated.
Be aware of hypoglycemia
Avoid if ALT level ≥ 3 ULN
Avoid vildagliptin
High dose may be needed

77. In patients with decompensated CLD
Insulin in the best line of therapy

80. 2/17/2016
,
.DCDC I7th,6-8 April,2016,Ras Elbarr,Domyat

81. 2/17/20
16

92. Doctor
PHARMACYDISPENSE
patientsFamily

93. Position Statement of the American Diabetes Association
(ADA) & the European Association for the Study of
Diabetes (EASD)
 Hypoglycaemia in type 2 diabetes was long thought to
be a trivial issue , as it occurs less commonly than in type
1 diabetes. However, there is emerging concern
based mainly on the results of recent clinical trials and
some cross-sectional evidence of increased risk of
brain dysfunction in those with repeated episodes
93
Diabetes Care, Diabetologia. 19 April 2012