This document discusses the management of diabetes in patients with concomitant liver disease. It notes that about half of patients with cirrhosis have diabetes due to insulin resistance caused by the liver disease. Lifestyle changes and metformin are recommended initially if liver disease is mild. Insulin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, and thiazolidinediones may be used, with monitoring needed due to potential side effects or altered drug metabolism in liver disease. Insulin requirements can vary depending on the stage of liver disease.

1. 1
Diabetes & liver
(Updates)
Alaa Wafa , MD.
Associate Professor of Internal Medicine
PGDIP DM Cardiff University UK
Diabetes & Endocrine Unit.
Mansoura University

2. AgendaAgenda
 Magnitude of the problem
 Spectrum of liver disease in type 2 diabetesSpectrum of liver disease in type 2 diabetes
 Management of diabetes in patients withManagement of diabetes in patients with
concomitant liver disease.concomitant liver disease.
 Management of liver disease in patients withManagement of liver disease in patients with
type 2 diabetes.type 2 diabetes.

3. Magnitude of the problem

4. Adapted from http://www.indexmundi.com/egypt/demographics_profile.html , https://www.cia.gov/library/publications/the-world-factbook/geos/eg.html , http://en.worldstat.info/World accessed 22-2-2014

5. Almost half of all
people with diabetes
live in just three
countries
China
India
USA
IDF
2013

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

7. Spectrum of liver disease inSpectrum of liver disease in
type 2 diabetestype 2 diabetes

8. Spectrum of liver disease in type 2Spectrum of liver disease in type 2
diabetesdiabetes
1. Abnormal liver enzymes
1.Elevation of (ALT),, is common in patients with type 2
diabetes ( 24%)( 24%).
2.Evaluation of asymptomatic individuals with mild
elevations of ALT and AST reveals that 98% have liver
disease most commonly, fatty liver disease and
chronic hepatitis
Belcher G, Schernthaner G: Changes in liver tests during 1-year treatment of patients with type 2
diabetes with pioglitazone, metformin or gliclazide. Diabet Med 22:973–979, 2005

10. Spectrum of liver disease in type 2 diabetesSpectrum of liver disease in type 2 diabetes
2. Non alcoholic fatty liver disease (NAFLD)
• It is defined as fatty liver disease in the absence of 20 g
alcohol/day.
• NAFLD consists of a spectrum of liver disease from
steatosis (fatty infiltration of the liver) to nonalcoholic
steatohepatitis (NASH), which consists of steatosis plus
inflammation, necrosis, and fibrosis.
• The prevalence of NAFLD in diabetes is estimated at 34–34–
74%74% and, in diabetes with obesity, at virtually 100%100%.
Pinto HC, et al: Nonalcoholic steatohepatitis: clinicopathological comparison with alcoholic hepatitis in
ambulatory and hospitalized patients. Dig Dis Sci 41:172–179, 1996

11. High prevalence of NAFLD* in Patients with
T2DM and Normal Plasma AST/ALT Levels
0
20
40
60
80
100
Non-obese Obese
Prevalence(%)
n=103
*Screened by the gold standard magnetic resonance and spectroscopy
(Portillo et al, submitted)

13. Prevalence of NAFLD in predominantly obese patient with
or without T2DM according to different diagnostic tools

14. Cardiovascular
disease
Cardiovascular
disease
OSAOSA
Vitamin D
deficiency
Vitamin D
deficiency
Vitamin D
deficiency
Vitamin D
deficiency
PCOSPCOS
HyperuricemiaHyperuricemia
Adenomatous
polyps
Adenomatous
polyps
Elevated ferritinElevated ferritin
HypothyroidismHypothyroidism
Pancreatic
steatosis
Pancreatic
steatosis

15. Metabolic Consequences of NAFLD

17. MR Elastography (MRE) in NAFLD

18. Spectrum of liver disease in type 2 diabetesSpectrum of liver disease in type 2 diabetes
3. Non alcoholic Steatohepatitis (NASH)
• While once considered a benign process, NASH has
been found to lead to cirrhosis and, in some cases, to
hepatocellular carcinoma.
• Of patients with NAFLD, 50% have NASH50% have NASH and 19% have19% have
cirrhosiscirrhosis at the time of diagnosis.
• Pathogenesis of steatosis :Insulin resistance resulting
in lipolysis, which increases circulating free fatty acids,
which are then taken up by the liver as an energy
source.
• The fatty acids overload the hepatic mitochondrial
oxidation system, leading to accumulation of fatty
acids in the liver.
Marchesini G, et al: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923, 2003

19. Red Flags for NASH
• Age
• Gender
• Hispanic
• HTN
• Obesity
• Diabetes
• ALT and AST level
• AST/ALT ratio
• Insulin level
• PNPLA3
Non lab test or imaging
study will be able predict
with 100% accurancy
For me, the more risk
factors .. The more
concerned I become

20. Natural history of NASH
NASHNASH
CirrhosisCirrhosis
Liver deathLiver death
FibrosisFibrosis
Liver
transplant
Liver
transplant
HCC
15-20%40-50%
2-3%/yr
30-40%
2-12% of US population Risk of death in NASH
1st
CVD
2nd
Cancer
3rd
Liver
• Currently, liver biopsy is the
only way to diagnose NASH
• Liver biopsy is classify such
as large population
• Impractical
• Expensive
• Invasive
• Variability
• Need for clinical predication
rules and novel biomarker of
NASH

21. Types of biomarkers
• Moacular
– Genomic
– Proteomic
• CK-18
• ELF
• HA RBP-4
• IU panel
• Younossi panel
– Lipiomic
• Oxidized FA
• Non HDL cholesterol
• Small dense LDL
– Metabolomic
– Hydrid panels
• NAFIC panel
• Imaging
– MR - based
• MRI-PDFF
• MRS
• MRE
• Diffusion-weighted
imaging
– ultrasound
• USG
• Transient USG
• ARFI
– CT

22. Spectrum of liver disease in type 2 diabetes
4. Hepatitis C in diabetes
Recent study shows that insulin resistance is a
risk factor for esophageal varicesrisk factor for esophageal varices in hepatitis C
virus cirrhosis.
Recent studies suggest that the core protein of
HCV impairs insulin receptor substrate signaling,
which plays an important role in the metabolic
effects of insulin.
Cammà C, et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology.
2009;49(1):195-203

23. Insulin Resistance and Hepatitis
• HCV infection contributes development of IR and
• Increase risk of development of T2DM
• Insulin resistance prevalence in CHC:
• 32% - 70%
• Insulin resistance associated with:
• Viral load
• fibrosis

24. Association of insulin resistance and
fibrosis progression
• IR associated with
moderate to serve
inflammation.
• HOMA increased
significantly with
fibrosis stage (p=0.001)
by logistic regression,
IR independently
associated with
significant fibrosis 0
3
6
9
12
15
Fibrosis (METAVIR)
F0-F1 F2 F3 F4
HOMA-IR
Moucari et al, Gastroenterology 2008; 134:416-423

25. Good News
• HCV eradication rates are now 90% or greater even for
cirrhosis
• Sustained virologic response associated with
decreased rates of progression to decompensation.
• Future is very bright. Newer direct acting antiviral
expected this year will be:
- All oral
-Minimal side effects
-Cure rate more than 90%
ADA Scientific Sessions San francisco 2014

26. 5. Cirrhosis in diabetes
The association of cirrhosis and diabetes is
complicated by the fact that cirrhosis itself is
associated with insulin resistance.
Wanless IR, Lentz JS: Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of
risk factors. Hepatology 12:1106–1110, 1990

27. Etiology of liver cirrhosis most frequentlyEtiology of liver cirrhosis most frequently
associated with diabetes mellitusassociated with diabetes mellitus

28. Spectrum of liver disease in type 2 diabetesSpectrum of liver disease in type 2 diabetes
6. Hepatocellular carcinoma in diabetes
• Numerous studies have confirmed a four foldfour fold
increased prevalenceincreased prevalence of hepatocellular carcinoma
in patients with diabetes as well as an increased
prevalence of diabetes in patients with HCC.
• Patients with HCC and DM have a mortality riskmortality risk
higherhigher than patients with HCC without DM.
• In another study involving 160 patients suffering
from HCC, those who had DM had a 1-year
mortality rate higher than those patients without
DM. Additionally, they had more extensive disease.
El-Serag HB, et al: Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
Gastroenterology 126:460–468, 2004

29. Hepatocellular carcinoma association
with diabetes
Hepatocellular
carcinoma
Diabetes
2-4 fold
1) Increased risk persists after
stratifying for age, gender,
ethnicity, viral hepatitis, alcohol,
iron overload
2) Synergistic with alcohol and
viral hepatitis.
J Natl cancer Inst 1997; Lawson DH, QJ Med 1986; La Vecchia C, Intl J cancer 1997; HO, J Natl
cancer Inst 1996; Yuan J M, Cancer 2004; Davila J A, Gut 2005; Hasson M M ,Hepatology 2002

30. Management of diabetes in patients
with concomitant liver disease

31. Management of diabetes in patients
with concomitant liver disease
• Few studies have evaluated what is the most effective
therapy for DM in cirrhotic patients and what is the
impact of treatment of DM on the clinical course of liver
disease.
• The treatment of DM of cirrhotic patients has particular
characteristics that make it different from type 2 DM
without liver disease:
(1) About half the patients have malnutrition
(2) When clinical DM is diagnosed, the patient has advanced liver
disease
(3) Most of the oral hypoglycemic agents are metabolized in the
liver
(4) Patients often have episodes of hypoglycemia.

32. Management of diabetes in patients
with concomitant liver disease
1. Lifestyle modification
• The initial treatment of patients suffering from
mild to moderate hyperglycemia and
compensated liver disease may be a lifestyle
change, since at this stage the insulin
resistance is a dominant factor.
• This may be compromised by poor nutritional
status and general health. More than 50% of
patients with severe liver disease are
malnourished.
Suzuki A, et al: Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J
Hepatol 43:1060–1066, 2005

33. Management of diabetes in patients
with concomitant liver disease
1. Lifestyle manifestation
• Low-glycemic, low-calorie diets with a weight loss of
1–2 kg/week1–2 kg/week seem reasonable.
• Physical exercise which improves insulin resistance
may not be an appropriate measure in patients with
active liver disease.

34. Management of diabetes in patients
with concomitant liver disease
2. Pharmacologic therapy:
• While there are theoretical concerns about
altered drug metabolism and hepatotoxicity,
only patients with evidence of liver failureonly patients with evidence of liver failure
such as ascites, coagulopathy, or
encephalopathy have altered drug
metabolism.

35. Management of diabetes in patients
with concomitant liver disease
A. Metformin:
• Metformin may be particularly useful in obese
patients in whom it may cause mild weight loss.
• It is relatively contraindicated in patients with
advanced liver disease or in drinkers because it may
predispose to lactic acidosis.
• Metformin has not been reported to cause
hepatotoxicity and has shown some benefit in
patients with NAFLD.
Nair S, et al: Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment
Pharmacol Ther 20:23–28, 2004

36. Management of diabetes in patients
with concomitant liver disease
B. Insulin secretagogues:
• Sulfonylureas are generally safe in patients with liver
disease but may not overcome the insulin resistance
and defects in insulin secretion seen in patients with
coexistent alcoholic liver disease and pancreatic
damage.
• Sulfonylureas with a short half-life such as glipizide or
glyburide are preferred in these patients.
• Patients with decompensated cirrhosis, may have a
reduced ability to counteract hypoglycemia, and thus,
the response to therapy should be monitored closely.

37. Management of diabetes in patients
with concomitant liver disease
B. Insulin secretagogues:
Clinical trials assessing the efficacy of
meglitinides in the treatment of patients with
liver disease have not been reported. The
pharmacokinetics and tolerability of
nateglinide in patients with cirrhosis is not
significantly different than in control subjects.
Repaglinide and nateglinide have not been
associated with hepatotoxicity.

38. Management of diabetes in patients
with concomitant liver disease
C. α-Glucosidase inhibitors:
• The α-glucosidase inhibitors may be
particularly useful in patients with liver disease
because they act directly on the
gastrointestinal tract to decrease carbohydrate
digestion and thus glucose absorption, thereby
decreasing postprandial hyperglycemia.
• There was also a reduction in blood ammonia
levels, which paralleled an increase in bowel
movement frequency.

39. Management of diabetes in patients
with concomitant liver disease
C. α-Glucosidase inhibitors:
 It was speculated that the increased bowel
frequency favored the proliferation of saccharolytic
bacteria while reducing the proliferation of
proteolytic bacteria, resulting in a reduction in
intestinal ammonia production.
 Acarbose frequently causes mild transient
elevations of ALT and, on rare occasions, severe
liver disease. While the labeling of acarbose has a
warning for patients with liver disease, it appears
to be safe and effective in patients with hepatic
encephalopathy and type 2 diabetes.
Gentile S, et al: A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol
Hepatol 3:184 –191, 2005

40. Management of diabetes in patients
with concomitant liver disease
D. Thiazolidinediones (TZD):
• TZDs may be especially useful because they enhance
insulin sensitivity, the underlying defect in NAFLD.
• There has been concern about their potential
hepatotoxicity because of the experience with
troglitazone.
• However, in pre-approval clinical trials of rosiglitazone
and pioglitazone, threefold elevations of ALT were
seen with the same frequency for rosiglitazone
(0.26%), pioglitazone (0.2%), and placebo (0.2 and
0.25%).
Harrison S, et al: A double-blind, placebo-controlled trial of pioglitazone in the treatment of non-alcoholic
steatohepatitis (NASH). Gastroenterology 128 (Suppl 2):A681, 2005

41. Management of diabetes in patients
with concomitant liver disease
D. Thiazolidinediones (TZD):
• It is currently recommended that serum ALT
levels be evaluated before the initiation of
rosiglitzone and pioglitazone therapy and that
therapy not be initiated if there is evidence of
active liver disease or if the serum ALT level
exceeds 2.5 times .
• Monitoring is recommended periodically
thereafter as clinically indicated rather than
every 2 months as previously recommended.

42. Management of diabetes in patients
with concomitant liver disease
E. Insulin:
• Insulin treatment is frequently required in patients with
diabetes and liver disease. Insulin requirements, however,
may vary.
• In patients with decompensated liver disease, the
requirement may be decreased due to reduced capacity for
gluconeogenesis and reduced hepatic breakdown of insulin.
• However, patients with impaired hepatic function may have
an increased need for insulin due to insulin resistance.
• In patients with hepatic encephalopathy who require high-
carbohydrate diets, resulting in postprandial hyperglycemia,
rapid-acting insulin analogs may be particularly useful.

43. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES

44. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
I. Abnormal liver function tests:
• All patients with type 2 diabetes should have an ALT
and AST test done as part of their initial evaluation.
• At least 95% of patients with a confirmed minor
elevation of ALT or AST have chronic liver disease
independent of the degree of elevation. Thus, it is
always necessary to obtain a specific diagnosis.
• The most likely etiologies of minor elevations of
ALT/AST are NAFLD, hepatitis C, hepatitis B, and
alcohol.

45. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
II. Fatty liver disease
 The diagnosis of NAFLD or NASH should be
suspected in any patient with type 2 diabetes,
especially if there are abnormal liver function tests.
It should be specifically looked for in all obese
patients with type 2 diabetes.
 Ultrasound studies may reveal a diffuse increase in
echogenicity, so-called “bright” liver.
 Most patients with NAFLD found incidentally or by
screening ultrasound have a normal ALT.

46. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
Treatment of NAFLD:
 Most patients do not need to be treated. Only
patients with biopsy-proved NASH or the risk
factors (reversed ALT/AST ratio,
hypertriglyceridemia & thrombocytopenia)
should be treated.
 The treatment consists of measures to lose
weight as well as pharmacologic intervention.

47. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
Treatment of NAFLD:
1. Exercise and weight reduction:
 Weight loss and exercise, which enhance insulin
sensitivity and result in reduction of steatosis.
 Rapid weight reduction, however, may increase
necrosis, inflammation, and fibrosis.
 The ideal rate of weight loss is not known, but 1.5
kg/week has been recommended.
 Recent studies have demonstrated that bariatric surgery
either improves or completely reverses steatosis in
patients with obesity with or without DM.

48. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
Treatment of NAFLD:
2. Pharmacologic therapy
 Pharmacologic therapy of NAFLD is evolving. While
many studies have shown improvement in steatosis.
There are neither long-term studies to determine
whether they alter the natural history of the disease
nor studies to indicate whether relapse occurs after
treatment withdrawal.
 Gemfibrozil, vitamin E, metformin, betaine,
silymarine, pioglitazone, rosiglitazone, atorvastatin,
losartan, orlistat, and pentoxifylline have all been
tried and have all been shown in small trials to
improve liver enzymes.

49. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
Pharmacologic therapy of NAFLD:
 Given that insulin resistance is central to the
pathogenesis of NAFLD, insulin sensitizing agents
should have utility, and there is increasing evidence that
they do.
 Metformin has shown mixed results in human trials with
some improvement in ALT but not in histology. At this
time, treatment with metformin is not recommended
outside of clinical trials.
 Five studies using pioglitazone from 16 to 48 weeks have
been published. All have shown improvement in serum
ALT and most in histology.
Lutchman G, et al: Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic
steatohepatitis: relationship to histological improvement. Clin Gastroenterol Hepatol 4: 1048–1052, 2006

52. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
Pharmacologic therapy of NAFLD:
 Three prospective controlled studies using
ursodeoxycholic acid, which reduces apoptosis and
has cytoprotective properties, have been conducted.
The results have been mixed.
 Statins may reduce hepatic fat content in patients with
hyperlipidemia and NASH.
Lindor K: Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized, placebo-
controlled study (Abstract). Gastroenterology 124 (Suppl.1):A336, 2003
Horlander J, Kwo P, Cummings O: Atorvastatin for the treatment of NASH. Gastroenterology 5:A-544 , 2001

53. MANAGEMENT OF LIVER DISEASE INMANAGEMENT OF LIVER DISEASE IN
PATIENTS WITH TYPE 2 DIABETESPATIENTS WITH TYPE 2 DIABETES
Pharmacologic therapy of NAFLD:
 Oxidative stress has been shown to be important in the
pathogenesis of NASH. It seems reasonable, therefore, to
try therapy with antioxidants.
 Pilot studies with vitamin E have been conducted with
promising results, but a meta-analysis of high-dose
vitamin E revealed an increase in overall mortality.
 Pentoxifylline is a compound that inhibits TNF-α. It is used
in the treatment of alcoholic hepatitis. A pilot study has
shown improvement in liver enzymes in patients with
NASH. However, the high incidence of side effects led to
early withdrawal in many patients.
Miller ER, 3rd, et al: Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med
142:37– 46, 2005

54. Current Pharmacological Options for ttt of NAFLD:
ADA scientific sessions 2014
Medication Results Outcome
Glucose lowering agents
Metformin Mixed results AST/ALT,,MRS,,Histology
piogltazone Effective Histology
Exenatide Effective(NAFLD) AST/ALT,,,MRS
Liraguide Effective(NAFLD) AST/ALT,,,CT
Lipid lowering agents
Statin Ineffective AST/ALT,,,Histology
Niacin Ineffective AST/ALT,,MRS
Fibrates Ineffective AST/ALT,,MRS
Orlistate Ineffective Histology
Vitamin E Mixed results AST/ALT,,,Histolog
Ursodesoxycholic acid Mixed results AST/ALT,,,Histology
Pentoxyfyllin Effective AST/ALT,,,Histology

55. Medical History and physical examMedical History and physical exam
AST/ALTAST/ALT
Liver
ultrasound
Liver
ultrasoundAssess risk of
NAFLD
Assess risk of
NAFLD
No farther
evaluation
Consider liver
ultrasound in
selected cases
Consider liver
ultrasound in
selected cases
Assess risk of
NAFLD
Assess risk of
NAFLD
Contemplate alternative
diagnostic tools (clinical models
biomarkers, alternative imaging
tests, etc.
Contemplate alternative
diagnostic tools (clinical models
biomarkers, alternative imaging
tests, etc.
Consider biopsyConsider biopsy
Recommend hepatology
referral to rule out other
cases of liver diseases
• Close flowing up
• Address lifestyle and
cv risk factors
NASHNo NASH
• Lifestyle intervention
• Consider pharmacological therapy
Abnormal
Normal
Rule out other
causes of
liver disease
Low riskHigh risk
NormalNAFLD
High risk
Low risk
NAFLD
Normal
Algorithm for the
Management of NAFLD
by Endocrinologistic
Recommend
Hepatology referral
Family history
T2DM ? Obesity?
Metabolic
Elevated

56. SummarySummary
 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.