Insulin Resistence in NAFL Disease.

Diagnose and Management

Oleh:
dr. H. Abimanyu, Sp.PD-KGEH.FINASIM
Div. GastroHepatology
SMF/Bagian. Ilmu Penyakit Dalam
FK Unlam/RSUD Ulin, Banjarmasin
o Steatosis (fatty liver) accumulation fat in the liver.

o Steatohepatitis progresses become associated inflammation.

o Fatty liver disease divided into:

Alcohol-related fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD).

o A threshold <20 g alcohol per day in women

<30 g in men allow a diagnosis of NAFLD.

o Inflammation is present non-alcoholic steatohepatitis (NASH) progress to

cirrhosis and hepatocellular carcinoma.

o NAFLD associated obesity, abnormal glucose tolerance and

Dyslipidaemia manifestation of the metabolic syndrome.
Insulin resistance in non-alcoholic fatty
liver disease
NAFLD strongly associated with both hepatic and adipose tissue insulin
resistance as well as reduced whole-body insulin sensitivity.

These studies 4550% reductions in glucose disposal, a measure of whole-

body insulin sensitivity, and an impaired ability of insulin to suppress endogenous
glucose production, indicative of hepatic insulin resistance.

NAFLD exhibit a defect in insulin suppression of free fatty acids (FFA), in

keeping with insulin resistance at the level of the adipocyte.

Insulin resistance defect in NAFLD, and that diminished insulin responsiveness

at the level of the adipocyte may contribute to hepatic steatosis by excess FFA
flux to the liver.
EPIDEMIOLOGY

o In Europe prevalence NAFLD 20-30% in the general population and 2.6-10% in the
paediatric population

o In Europe prevalence NASH 5%.

o Fatty liver develops in 46-90% of heavy alcohol users

up to 94% of obese individuals.

o NAFLD the most common cause abnormal LFTs in many developed countries.

o Incidence NAFLD and NASH rising in children and adolescents.

EPIDEMIOLOGY

o NAFLD most common liver disease in Western countries. 20%33% general

population.

o In China prevalence 15%30%.

o Worldwide prevalence NAFLD increased rapidly parallel with regional trends

of obesity, type2 diabetes and metabolic syndrome.

o Prevalence NAFL in children 4.2%-9.6%.

o Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic

syndrome and NAFLD closely related
EPIDEMIOLOGY

J Clin Gastroenterol Volume 48, Number 6, July 2014

DEFINITIONS
Patophysiology

Int. J. Mol. Sci. 2014, 15, 7352-7379; doi:10.3390/ijms15057352

Multi-hit hypothesis for nonalcoholic
steatohepatitis (NASH).

oxLDL: oxidized low-density lipoprotein

TLR: Toll-like receptor.

World Gastroenterology Organisation, 2012

Pivotal role of insulin resistance in non-
alcoholic fatty liver disease pathophysiology.

World J Gastroenterol 2014 July 14; 20(26): 8377-8392

Diagram of potential sources of and mechanisms for
the accumulation of fat in the liver

J Clin Endocrinol Metab, December 2006, 91(12):4753 4761

Disease progression from NAFLD to NASH
to cirrhosis/liver failure and HCC.
Disease progression from NAFLD to
NASH to cirrhosis/liver failure and HCC.
Risk Factors
ETIOLOGY

Risk factors developing fatty liver:

o Metabolic Syndrome: type 2 diabetes or impaired glucose tolerance, central obesity,

dyslipidaemia, raised blood pressure

o Polycystic ovarian syndrome

o Alcohol excess

o Starvation or rapid weight loss, including following gastric bypass surgery (presumed
due to sudden release of free fatty acids into the bloodstream)

o Total parenteral nutrition and refeeding syndrome

o Hepatitis B and C, HIV

Risk factors

o Medication:

Amiodarone

Tamoxifen

Glucocorticoids

Tetracycline

Oestrogens

Methotrexate

Thallium
Risk factors

o Metabolic disorders Wilson's disease

Glycogen storage disorders
Abetalipoproteinaemia and hypobetalipoproteinaemia
Galactosaemia
Hereditary fructose intolerance
Homocystinuria
Refsum's disease
Systemic carnitine deficiency
Tyrosinaemia
Weber-Christian disease
Natural history of nonalcoholic fatty liver
disease
Presentation

Examination

Hepatomegaly is very common.

Splenomegaly with or without portal hypertension may occur with
cirrhosis.
Signs of chronic liver disease may be seen in patients with cirrhosis
(ascites, oedema, spider naevi).
 INVESTIGATIONS
A definitive diagnosis by liver biopsy and histopathological analysis.
Diagnostic
Blood tests
LFTs: mildly raised ALT is often the first change relative to AST, but this tends to reverse if disease
progresses, and then ALT falls. Up to 50% of patients can have normal ALT and AST levels.[2]

Further LFT changes if alcohol is the cause (raised gamma-glutamyl transpeptidase (GGT))

Other blood tests are part of the work-up for associated causes:[4]

Fasting lipids (usually raised)

Fasting glucose

FBC

Viral studies (hepatitis)

Iron studies

Caeruloplasmin

Autoimmune studies (ANA, ASMA may be raised in NASH)

Diagnostic imaging
These techniques may be used to define extent and course of disease.
Steatohepatitis is usually diffuse, whereas steatosis may be focal or diffuse:

Ultrasound:

Shows a hyper-echogenic, bright image.

Ultrasound has some diagnostic accuracy in detecting steatosis but is not good at
distinguishing NASH and fibrosis within NAFLD.[7]

CT scanning may be helpful to monitor the course of the disease.

MRI scan can be used to exclude fatty infiltration and the course and extent of
this and other liver disease (used with phase-contrast imaging).
Biomarkers

Combinations of non-invasive biomarkers have been tested to diagnose steatosis

accurately and reduce the need for liver biopsy
Liver Biopsy

The only definitive test. It is performed to confirm diagnosis, exclude other causes,
assess extent and predict prognosis.

Severity can be scored.

MANAGEMENT
A 10-minute consultation on NAFLD
o Diagnose NAFLD with confidence:
If the patient has classical risk factors for the metabolic syndrome.
If other common or treatable causes of abnormal LFTs have been excluded.

o Explain:
The abnormal liver findings (inflammation that is probably due to excess fat).
The importance of lifestyle measures (such as gradual weight loss, regular exercise, dietary measures, and alcohol
cessation).
The drug treatments for hyperglycaemia, hypertension, and lipid-lowering.

o Assess for:
Cardiovascular risk.
Any hepatic complications.
Anthropometry (including waist circumference).
Repeat any abnormal blood tests.

o Consider specialist referral where:

There is uncertainty about the diagnosis.
There are signs of advanced liver disease.
There is GP or patient concern (for example, on the exact diagnosis).
Advice about pharmacological therapies is required.
AASLD Practice Guideline

Lifestyle intervention
Recommendations:
Weight loss generally reduces hepatic steatosis, achieved either by
hypocaloric diet alone or in conjunction with increased physical
activity. (Strength 1, Evidence - A)
Loss of at least 3-5% of body weight appears necessary to improve
steatosis, but a greater weight loss (up to 10%) may be needed to
improve necroinflammation. (Strength 1, Evidence - B)
Exercise alone in adults with NAFLD may reduce hepatic steatosis
but its ability to improve other aspects of liver histology remains
unknown.(Strength 1, Evidence - B)
Diet

Gradual weight loss is important (approximately 1-2 pounds per week).

Diets should have a high protein:calorie ratio.

A typical low-fat diabetes-type diet is recommended.

Abstinence from alcohol is recommended for all types of steatosis and steatohepatitis.
Exercise

Exercise with diet increases muscle mass and increases insulin sensitivity.

Improving cardiovascular fitness and weight training should improve NASH but,
as yet, there are no randomised trials to confirm that this works in practice (the
logic being that this helps reverse the underlying derangements).
Drugs

Trials are underway to evaluate lipid-lowering agents and drugs which are insulin
sensitisers.

Improvements histologically and biochemically have been shown with

thiazolidinediones, metformin (radiological and biochemical improvement),
gemfibrizol (no histological data) and atorvastatin.

Orlistat improves histological and biochemical improvements but studies are only
short-term so far.
AASLD Practice Guideline
Insulin sensitizing agents.

Metformin
Metformin has no significant effect on liver histology and is not
recommended as a specific treatment for liver disease in adults with NASH.
(Strength 1, Evidence - A)

Pioglitazone
Can be used to treat steatohepatitis in patients with biopsy-proven NASH.
However, it should be noted that majority of the patients who participated
in clinical trials that investigated pioglitazone for NASH were non-diabetic
and that long term safety and efficacy of pioglitazone in patients with NASH
is not established. (Strength 1, Evidence - B)
AASLD Practice Guideline

Vitamin E (alpha-tocopherol)
Administered at daily dose of 800 IU/day improves liver histology in
non-diabetic adults with biopsy-proven NASH and therefore it should
be considered as a first-line pharmacotherapy for this patient
population. (Strength -1, Quality - B)
Until further data supporting its effectiveness become available,
vitamin E is not recommended to treat NASH in diabetic patients,
NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis
(Strength - 1, Quality - C)
AASLD Practice Guideline

Statin
Given the lack of evidence to show that patients with
NAFLD and NASH are at increased risk for serious drug-
induced liver injury from statins, statins can be used to
treat dyslipidemia in patients with NAFLD and NASH.
(Strength 1, Quality B)
 UDCA

UDCA treatment has the potential to improve NAFLD as several

markers were improved following its utilization.
ER stress is a cell survival response and requires extensive
experimental analysis to elucidate the potency and timing of ER
stress targeted drug administration.
Mechanism of action
 Reduction of hepatic lipids might be due to their excretion in feces, followed by
enhanced utilization of glucose for the synthesis of fatty acids and cholesterol.
Ursodeoxycholic acid should be effective for the treatment of type 2 diabetes
mellitus accompanying hepatic steatosis.
These results indicate that UDCA ameliorates hyperglycemia and hyperinsulinemia
by improving hepatic insulin resistance and steatosis
Treatment of NASH with UDCA for 12 months resulted in
significant improvement in alkaline phosphatase, ALT, GGT,
and hepatic steatosis.
RECENT FINDINGS

Some existing medications, including pioglitazones and angiotensin

receptor antagonists, may be repurposed to help treat this condition.
Vitamin E may improve histology in NASH, but safety issues limit its use.
Recently, a number of novel agents specifically targeting nonalcoholic
fatty liver disease pathogenesis have entered clinical trials, including
the farnesoid X receptor agonist obeticholic acid, which has shown
significant histological improvements in steatohepatitis and fibrosis.
Surgery
Bariatric surgery can bring about histological and biochemical improvements in NASH.

Recent studies have not shown worsening hepatic function seen in earlier studies of
bypass surgery (for example, gastric bypass with Roux-en-Y) in NASH.
Follow-up
All patients with chronic liver disease or at risk of disease progression should be
followed up. Follow-up with the GP is appropriate. Follow-up should aim to detect any
progression of disease (signs of liver disease, abnormal blood results, development of
symptoms).
Education of patients should be an ongoing process. Avoidance of alcohol and
hepatotoxic drugs should be part of this.
Promotion of gradual weight loss and an increase in exercise should continue.
Complications
Steatohepatitis can progress to cirrhosis and liver failure just like any chronic liver
disease.
Progression to cirrhosis is more rapid when there is alcoholic liver disease or,
indeed, any form of concomitant liver disease (for example, chronic viral
hepatitis). Poor control of hyperlipidaemia or diabetes will also accelerate
progression of fibrosis.
Hepatocellular carcinoma can occur at the same rate as with other forms of liver
disease.
The Diagnosis and Management of Non-alcoholic Fatty Liver
Disease: Practice Guideline by the American Gastroenterological
Association,
American Association for the Study of Liver Diseases, and American
College of Gastroenterology

Recommendation
1. Ongoing or recent alcohol consumption 21 drinks on average per
week in men and 14 drinks on average per week in women is a
reasonable definition for significant alcohol consumption when
evaluating patients with suspected NAFLD in clinical practice.
(Strength 2, Quality - C) Recommendations
Recommendation

2. When patients with unsuspected hepatic steatosis detected on imaging

have symptoms or signs attributable to liver disease or have abnormal liver
biochemistries, they should be evaluated as though they have suspected
NAFLD and worked-up accordingly. (Strength 1, Evidence - A)

3. In patients with unsuspected hepatic steatosis detected on imaging who

lack any liver-related symptoms or signs and have normal liver
biochemistries, it is reasonable to assess for metabolic risk factors (e.g.,
obesity, glucose intolerance, dyslipidemia) and alternate causes for
hepatic steatosis such as significant alcohol consumption or medications.
(Strength 1, Evidence - A)

4. In patients with unsuspected hepatic steatosis detected on imaging who

are asymptomatic and have normal liver biochemistries, a liver biopsy
cannot be recommended. (Strength 1, Evidence - B)
Recommendation

5. Screening for NAFLD in adults attending primary care clinics or high-

risk groups attending diabetes or obesity clinics is not advised at this
time due to uncertainties surrounding diagnostic tests and treatment
options, along with lack of knowledge related to the long-term
benefits and cost-effectiveness of Screening. (Strength 1, Evidence -
B)

6. Systematic screening of family members for NAFLD is currently not

recommended. (Strength 1, Evidence - B)

7. When evaluating a patient with suspected NAFLD, it is essential to

exclude competing etiologies for steatosis and co-existing common
chronic liver disease. (Strength 1, Evidence - A)
Recommendation

8. Persistently high serum ferritin and increased iron saturation,

especially in the context of homozygote or heterozygote C282Y
HFE mutations may warrant a liver biopsy. (Strength 1, Evidence -
B)

9. High serum titers of autoantibodies in association with other

features suggestive of autoimmune liver disease (very high
aminotransferases, high globulin) should prompt a more complete
work-up for autoimmune liver disease. (Strength 1, Evidence - B)
Recommendation

10. As the metabolic syndrome predicts the presence of

steatohepatitis in patients with NAFLD, its presence can be used to
target patients for a liver biopsy. (Strength 1, Evidence - B)

11. NAFLD Fibrosis Score is a clinically useful tool for identifying NAFLD
patients with higher likelihood of having bridging fibrosis and/or
cirrhosis. (Strength 1, Evidence - B)

12. Although serum/plasma CK18 is a promising biomarker for

identifying steatohepatitis, it is premature to recommend in routine
clinical practice. (Strength 1, Evidence - B)
Recommendation

13. Liver biopsy should be considered in patients with NAFLD who are
at increased risk to have steatohepatitis and advanced fibrosis.
(Strength 1, Evidence - B)

14. The presence of metabolic syndrome and the NAFLD Fibrosis Score
may be used for identifying patients who are at risk for
steatohepatitis and advanced fibrosis. (Strength 1, Evidence - B)

15. Liver biopsy should be considered in patients with suspected NAFLD

in whom competing etiologies for hepatic steatosis and co-existing
chronic liver diseases cannot be excluded without a liver biopsy.
(Strength 1, Evidence - B)
Recommendation

16. Weight loss generally reduces hepatic steatosis, achieved either by

hypocaloric diet alone or in conjunction with increased physical
activity. (Strength 1, Evidence - A)

17. Loss of at least 35% of body weight appears necessary to improve

steatosis, but a greater weight loss (up to 10%) may be needed to
improve necroinflammation. (Strength 1, Evidence - B)

18. Exercise alone in adults with NAFLD may reduce hepatic steatosis
but its ability to improve other aspects of liver histology remains
unknown. (Strength 1, Evidence - B)
Recommendation

19. Metformin has no significant effect on liver histology and is not

recommended as a specific treatment for liver disease in adults
with NASH. (Strength 1, Evidence - A)

20. Pioglitazone can be used to treat steatohepatitis in patients with

biopsy-proven NASH. However, it should be noted that majority of
the patients who participated in clinical trials that investigated
pioglitazone for NASH were nondiabetic and that long term safety
and efficacy of pioglitazone in patients with NASH is not
established. (Strength 1, Evidence - B)h NASH. (Strength 1,
Evidence - A)
Recommendation

21. Vitamin E (-tocopherol) administered at daily dose of 800 IU/day

improves liver histology in non-diabetic adults with biopsy-proven
NASH and therefore it should be considered as a first-line
pharmacotherapy for this patient population. (Strength 1, Quality
B)

22. Until further data supporting its effectiveness become available,

vitamin E is not recommended to treat NASH in diabetic patients,
NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
(Strength 1, Quality C)
Recommendation

23. UDCA is not recommended for the treatment of NAFLD or NASH.

(Strength 1, Quality B)

24. It is premature to recommend omega-3 fatty acids for the specific

treatment of NAFLD or NASH but they may be considered as the
first line agents to treat hypertriglyceridemia in patients with NAFLD.
(Strength 1, Quality B)
Recommendation

25. Foregut bariatric surgery is not contraindicated in otherwise eligible

obese individuals with NAFLD or NASH (but without established
cirrhosis). (Strength 1, Quality A)

26. The type, safety and efficacy of foregut bariatric surgery in

otherwise eligible obese individuals with established cirrhosis due to
NAFLD are not established. (Strength 1, Quality B)

27. It is premature to consider foregut bariatric surgery as an

established option to specifically treat NASH. (1B) AGA June 2012
AGA 1599
Recommendation

28. Patients with NAFLD should not consume heavy amounts of

alcohol. (Strength 1, Quality B)

29. No recommendation can be made with regards to non-heavy

consumption of alcohol by individuals with NAFLD. (Strength 1,
Quality B)

30. Given the lack of evidence to show that patients with NAFLD and
NASH are at increased risk for serious drug-induced liver injury from
statins, statins can be used to treat dyslipidemia in patients with
NAFLD and NASH. (Strength 1, Quality B)
Recommendation

31. Until RCTs with histological endpoints prove their efficacy, statins
should not be used to specifically treat NASH. (Strength 1, Quality
B)

32. When steatosis and steatohepatitis are evident in patients with

other types of chronic liver disease, it is important to assess for
metabolic risk factors and alternate etiologies for hepatic steatosis.
(Strength 1, Quality B)

33. In patients with other types of chronic liver diseases who have co-
existing NAFLD and NASH, there are no data to support the use of
vitamin E or pioglitazone to improve the liver disease. (Strength 1,
Quality B) AGA 1600 AGA GASTROENTEROLOGY Vol. 142, No. 7
Recommendation

34. Patients with NASH cirrhosis should be screened for

gastroesophageal varices according to the AASLD/ACG practice
guidelines.181(Strength 1, Quality B)

35. Patients with NASH cirrhosis should be considered for HCC

screening according to the AASLD/ACG practice
guidelines.182(Strength 1, Quality B)

36. Current evidence does not support routinely repeating a liver

biopsy in patients with NAFL or NASH. (Strength 2, Quality C)
Recommendation

37. Children with fatty liver who are very young or not overweight
should be tested for monogenic causes of chronic liver disease
such as fatty acid oxidation defects, lysosomal storage diseases
and peroxisomal disorders, in addition to those causes considered
for adults. (Strength 2, Quality C)

38. Low serum titers of autoantibodies are often present in children with
NAFLD, but higher titers, particularly in association with higher serum
aminotransferases and high globulin should prompt a liver biopsy to
evaluate for possible autoimmune hepatitis. (Strength 2, Quality
B)
Recommendation

39. Due to a paucity of evidence, a formal recommendation cannot be

made with regards to screening for NAFLD in overweight and obese
children despite a recent expert committee recommendation for
biannual screening for liver disease with liver enzyme measurements in
this population. (Strength 1, Quality B).

40. Liver biopsy in children with suspected NAFLD should be performed in

those where the diagnosis is unclear, where there is possibility of
multiple diagnoses, or before starting therapy with potentially
hepatotoxic medications. (Strength 1, Quality B)

41. A liver biopsy to establish a diagnosis of NASH should be obtained prior

to starting children on pharmacologic therapy for NASH. (Strength 2,
Quality C).
Recommendation

42. Pathologists interpreting pediatric NAFLD biopsies should recognize the

unique pattern frequently found in children to not misidentify pediatric
NAFLD. (Strength 1, Quality B).

43. Intensive lifestyle modification improves aminotransferases and liver

histology in children with NAFLD and thus should be the first line of
treatment. (Strength 2, Quality B)

44. Metformin at 500 mg twice daily offers no benefit to children with

NAFLD and thus should not be prescribed. The effect of metformin
administered at a higher dose is not known. (Strength 1, Quality B)

45. Vitamin E 800 IU/day (RRR tocopherol) offers histological benefits to

children with biopsy-proven NASH or borderline NASH but confirmatory
studies are needed before its use can be recommended in clinical
practice. (Strength 1, Quality B)
Prognosis
The prognosis depends on the stage of disease.

Steatosis
Has a good prognosis with abstinence and gradual weight loss.

Cirrhosis develops in 1% to 2% over 20 years.

Central obesity and insulin resistance are risk factors for diabetes mellitus, and
cardiovascular and renal disease.

Steatohepatitis
10% to 12% of patients will progress to cirrhosis within eight years.[13] This is similar to the
rate of progress towards cirrhosis in alcohol-related liver disease.
Prevention
It may be possible to prevent steatohepatitis by actively screening for patients at
risk of steatosis and educating them about diet, exercise and alcohol.
Practice tips
Fatty liver is not an entirely benign condition.

At-risk patients should be identified and screened for liver disease (particularly steatosis
and steatohepatitis). This will involve history, examination and blood tests but may
involve further investigation if results are abnormal or the risk of liver disease is high.

All patients at risk of steatosis or steatohepatitis should be educated about the

condition (causes, management, prevention and follow-up).

Patients with steatosis or steatohepatitis should be appropriately managed, educated

and, in a few cases, referred.

Beware of even minor abnormalities of liver function in at-risk groups.

SUMMARY

Diet / lifestyle modification remains the mainstay of treatment. For

patients with NASH and advanced fibrosis, current liver-directed
pharmacotherapy with vitamin E and pioglitazone offer some benefits;
obeticholic acid appears promising and is currently being tested.
Comorbidities must be diagnosed and treated; cardiovascular disease
remains a primary cause of death in these patients.
Thank You