NON ALCOHOLIC FATTY LIVER DISEASE

DR SARIU ALI

MEDICAL OFFICER, IGMH

SUPERVISOR : DR FATHIMATH NADHIYA , CONSULTANT IN INTERNAL MEDICINE, IGMH

DEFINITION Nonalcoholic Fatty Liver Disease (NAFLD)

(a) there is evidence of hepatic steatosis, either by imaging or by histology and

(b) (b) there are no causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication or hereditary disorders

Histologically further categorized into

Nonalcoholic Fatty Liver (NAFL)

Nonalcoholic Steatohepatitis (NASH)

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Most common of All liver Disorders

Most frequent cause of chronic liver disease most common cause of End stage Liver Disorder Needing liver transplantation.

Present in up to 75% of individuals with obesity and type 2 Diabetes

Present in 3% of children and > 50%obese children.

Nonalcoholic Fatty Liver (NAFL)Evidence of Hepatic steatosis either by imaging or Histology (> 5% of hepatocytes histologically) without any other Cause for secondary Fat Accumulation with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes or no evidence of fibrosis.

The risk of progression to cirrhosis and liver failure is minimal.

Nonalcoholic steatohepatitis (NASH)Presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning) with or without fibrosis. This can progress to cirrhosis, liver failure and rarely liver cancer

METABOLIC SYNDROME ; ALARMING FIGURES

NFLD : A BURDEN WORLDWIDE

ENVIRONMENTAL FACTORS FOR A FATTY WORLD

ETHNIC FACTORS AND NAFLD

PREVALENCE OF NAFLD IN HIGH RISK GROUPS

Population studied prevalence of NAFLD

excessive BMI and visceral obesity are recognized risk factors Severe obesity undergoing bariatric surgery

90% NAFLD5% of patients may haveunsuspected cirrhosis

An ultrasonographic study of patients with T2DM

69% prevalence of NAFLD

Another study 127 of 204 diabetic patients displayed fatty infiltration on ultrasound,

62% fatty infiltration and 87% those who consented to biopsy had histologic confirmation of NAFLD

Individuals with dyslipidemia attending lipid clinics

prevalence of NAFLD estimated to be 50%.

PATHOGENESIS AND RISK FACTORS

Insulin resistance is related to obesity and is central to the pathogenesis of NAFLD.

In addition, oxidative stress and cytokines are important contributing factors, together resulting in steatosis and progressive liver damage in genetically susceptible individuals.

Key histologic components of NASH are steatosis, hepatocellular ballooning, and lobular inflammation

MULTI-HIT HYPOTHESIS

RISK FACTORS AND ASSOCIATED CONDITIONS

NASH SCORING SYSTEM IN MORBID OBESITY

PROGNOSIS AND COMPLICATIONS

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

Concurrence of NAFLD with hepatitis C or human immunodeficiency virus (HIV) worsens their prognoses and decreases their responses to therapy.

Liver biopsy may indicate the severity of disease, but only fibrosis, and not inflammation or necrosis, has been confirmed to predict the disease prognosis.

End-stage NASH is an often under-recognized cause of cryptogenic cirrhosis

NASH-related (cryptogenic) cirrhosis increases the risk of hepatocellular carcinoma (HCC).

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)

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

Independent predictors for progression of fibrosis:

Age > 45–50BMI > 28–30 kg/m2Degree of insulin resistanceDiabetesHypertension

The degree of fibrosis on liver biopsy (stage) is predictive of the prognosis

FIBROSIS STAGE : INDEPENDENT FACTOR FOR LIVER MORTALITY

NASH SURVIVAL RATES IN COMPARISON WITH SIMPLE STEATOSIS AND ALCOHOLICSTEATOHEPATITIS (ASH)

Causes of mortality in cirrhotic NASH patients:— Liver failure— Sepsis— Variceal hemorrhage— HCC— Cardiovascular disease

DIAGNOSISPATIENT HISTORY AND CLINICAL EVALUATION

Asymptomatic

vague symptoms of fatigue, malaise, and abdominal discomfort.

Detailed patient history of alcohol— Appropriate specialized questionnaires or scoring systems for the evaluationof alcohol consumption Eg.— CAGE questionnaire

Abdominal obesity Enlarged liver RUQ tenderness on palpation

Central obesity correlates with severity of inflammation on biopsy, and dorsocervical lipohypertrophy (buffalo hump) correlates with hepatocyte injury.

In case of progression/advanced liver disease: spider angiomas, ascites, hepatomegaly, splenomegaly, palmar erythema, jaundice, hepatic encephalopathy.

Physical exam

The presence of any of the following, especially with a history of abnormal AST/ALT, should lead to a work-up for NAFLD/NASH:— Presence of obesity, especially morbid obesity (BMI > 35)

— Diagnosis of type 2 diabetes mellitus

— Diagnosis of metabolic syndrome

— History of obstructive sleep apnea

— Presence of insulin resistance

— Chronic elevation of AST/ALT, otherwise unexplained

CALCULATION OF INSULIN RESISTANCE

ROUTINE LABORATORY FINDINGS AND IMAGING TESTS

Elevated ALT and AST: In 10% of NASH patients, ALT and AST may

be normal, especially with simple steatosis.AST/ALT ratio < 1—this ratio is usually > 2 in

alcoholic hepatitis.

An abnormal ferritin level in the presence of normal transferrin saturation should always suggest a need to rule out NASH.

Tests to exclude: secondary causes of hepatic steatosis

Imaging - confirming fat accumulation in the liver:

• The magnetic resonance imaging (MRI) test has a quantitative value, but cannot distinguish between NASH and ASH.

• Ultrasound is the usual screening test for fatty liver.

WHEN TO OBTAIN A LIVER BIOPSY IN PATIENTS WITH NAFLD?

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

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)

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 excludedwithout a liver biopsy. (Strength – 1, Evidence - B)

NASH CLINICAL RESEARCH NETWORK HISTOLOGICAL SCORING SYSTEM

DIAGNOSTIC TESTS FOR FATTY LIVER

A wide variety of attempts have been made to develop scoring systems or imaging techniques that will allow noninvasive diagnosis of NASH and avoid the need for a liver biopsy.

Specialized imaging modalities, including FibroScan, using a novel “controlled attenuation parameter,” and positron emission tomography (PET) scanning suffer from the same limitations of limited availability, high cost, and lack of sufficient controlled data.

NON-INVASIVE ASSESSMENT OF STEATOHEPATITIS AND ADVANCED FIBROSIS IN NAFLD

NON-INVASIVE ASSESSMENT OF STEATOHEPATITIS AND ADVANCED FIBROSIS IN NAFLD

The NAFLD Fibrosis Score Enhanced Liver Fibrosis (ELF)

panel Transient Elastography Circulating levels of cytokeratin-18

(CK18)

NAFLD FIBROSIS SCORE

http://nafldscore.com

Age

BMI

Hyperglycemia

Platelet count

Albumin

AST

ALT

< -1.455: 90% sensitivity and 60% specificity to

exclude advanced fibrosis

> 0.675: 67% sensitivity and 97% specificity to identify

the presence of advanced fibrosis.

DIAGNOSTIC STRATEGY FOR NASH

MANAGEMENT

Therapeutic rationale

Targets for therapy : insulin resistance and oxidative stress

Goals of treatment: reduce the histologic features and improve insulin resistance and liver enzyme levels.

LIFESTYLE INTERVENTION

Weight loss generally reduces hepatic steatosis, achieved either by hypocaloric diet alone or in conjunction with increased physical activity.

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.

Exercise alone in adults with NAFLD may reduce hepatic steatosis but its ability to improve other aspects of liver histology remains unknown.

AVOID FRUCTOSE Fructose (+++++ in corn syrup)

Soda, canned industrial dishes

Experimental Data

Mice fed with fructose devaloped more severe inflamatory injuries compare to High fat diet Mice

-kholi, Hepatology 2010-

Human Data

In patients with NASH fructose consumption is associated with liver fibrosis

-Abdel malek Hepatology 2010-

INSULIN SENSITIZING AGENTSMETFORMIN

A recent meta analysis concluded that 6–12 months of metformin plus lifestyle intervention did not improve aminotransferases or liver histology, compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes.

June 2012 AGA 1597

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)

INSULIN SENSITIZING AGENTSTHIAZOLIDINEDIONES

•Rosiglitazone**: improved enzymes and steatosis, but not inflammation

•Pioglitazone:***+weight gain, but significantly improved aminotransferases, steatosis, ballooning, and inflammation

*Uygun, et al Aliment Pharm Ther 2004

*Nair, et al Aliment Pharm Ther 2004 **Ratziu, et al Gastroenterology 2008 ***Sanyal, et al NE J Med 2010

PIVENS STUDYPioglitazone , Vitamin E, placebo

96 weeks

Adults • with NASH• without DM, cirrhosis, Hep C, heart failure• limited alcohol intake over previous 5 years

Randomized trial• Pio group: 80• Vit E group: 84• Placebo: 83

Sanyal et al, New England J of Medicine 2010

PRIMARY OUTCOME

Vitamin E vs placebo

43% improvement vs 19%: significant

(Steatosis, lobular inflammation, hepatocellular ballooning and fibrosis)

Pio vs placebo

34% improvement vs 19%: not significant

Sanyal et al, New England J of Medicine 2010

SECONDARY OUTCOME

Vitamin E vs placebo

• Also reduction in SGOT/SGPT

Pio vs placebo• Reduction in SGOT/SGPT• Reduction in steatosis,

lobular inflammation• Improvement in IR• Increase in weight that did

not resolve after discontinuance of Pio

Sanyal et al, New EngJ of Med 2010

PIVEN CONCLUSIONSVitamin E was superior to placebo in adults with NASH and without DM

Pioglitazone may have a role in treating patients with biopsy-proven NASH, however long term safety and efficacy has not been established

Sanyal et al, New EnglJ of Med 2010

AASLD RECOMMENDATIONS:Pio can be used to treat certain patients with biopsy-proven NASH who do not have DM but long term safety and efficacy has not been established

Vitamin E 800 IU/day improves liver histology in NASH pts

• Not recommended to treat NASH in those with other chronic liver diseases, diabetics, those with NASH cirrhosis or cryptogenic cirrhosis, NAFLD without biopsy

Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in subjects with NASH.

Vitamin E is an anti-oxidant and has been investigated to treat NASH

the use of vitamin E is associated with a decrease in aminotransferases in subjects with NASH,

causes improvement in steatosis, inflammation, and ballooning and resolution of steatohepatitis in adults with NASH

vitamin E has no effect on hepatic fibrosis.

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)

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)

VITAMIN E: OTHER CONCERNSMeta-analysis* including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortality

Vitamin E** > 400 IU/day increases risk of prostate cancer in relatively healthy men

*Miller et al Annals of Internal Medicine 2005

** Klein, et al, JAMA 2011

URSODEOXYCHOLIC ACID (UDCA), OMEGA-3 FATTY ACIDS

UDCA : no histologic benefit

UDCA is not recommended for the treatment of NAFLD or NASH. (Strength – 1, Quality – B)

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)

A large multicenter study of one omega-3 fatty acid (eicosapentanoic acid) to treat NASH is ongoing in the United States

STATIN USE IN PATIENTS WITH NAFLD AND NASH

CVD common cause of death for NAFLD and NASH

Stratify risks and treat accordingly

Several studies show NAFLD and NASH pts are not at increased risk of liver injury over general population*

Until RCTs with histological endpoints prove their efficacy, statins should not be used to specifically treat NASH.

(Strength – 1, Quality – B)

*Chalasani, et al. Am J Gastro 2012

GREACE STUDY*

Concluded statins significantly improve liver biochemistries and CV outcomes in pts with elevated enzymes likely due to NASH

Athyros et al Lancet 2010

AASLD RECOMMENDATION ON STATINS

“Given lack of evidence that patients with NAFLD and NASH are at increased risk for serious drug-induced liver injury from statins, they can be used to treat dyslipidemia in patients with NAFLD and NASH.”

BARIATRIC SURGERY

No RCTs

Cochrane review 2010: lack of RCTs prevents definitive assessment of risks/benefits

Prospective study*• 381 adults with severe obesity, fibrosis score<3• Clinical, metabolic, liver biopsy comparisons at 1 year

and 5 years• Significant improvement in steatosis, ballooning,

resolution of probable/definite NASH at 1 and 5 years• Small but significant increase of fibrosis score at 5

years (96% had improvement) *Mathurin et al Gastroenterology 2009

AASLD RECOMMENDATION ON BARIATRIC SURGERYPremature to consider foregut surgery as an option to specifically treat NASH

Foregut surgery is not contra-indicated in otherwise eligible pts with NASH or NAFLD WITHOUT cirrhosis

For those with cirrhosis: type, safety and efficacy of foregut surgery is not established

MONITORING STRATEGYDISEASE PROGRESSION AND COMPLICATIONS CAN BE DETECTED DURING THE FOLLOW-UP AS INDICATED

MISCELLANEOUS RECOMMENDATIONSPERTINENT TO CLINICAL PRACTICE

Patients with NASH cirrhosis should be screened for gastroesophageal varices according to the AASLD/ACG practice

guidelines. (Strength – 1, Quality – B)

Patients with NASH cirrhosis should be considered for HCC screening according to the AASLD/ACG practice guidelines. (Strength – 1, Quality – B)

Current evidence does not support routinely repeating a liver

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

SUMMARY

Metabolic Syndrome and NAFLD has reached epidemic proportions

NFLD can lead to Cirrhosis and HCC

Patients with NFLD have lower overall survival

The diagnosis should be sought in all patients who present with risk factors for NASH. Not all patients with risk factors will have NAFLD or NASH, and not all patients with NASH will have standard risk factors.

NFLD is a cofactor of liver progression

Lifestyle diet and Exercise still represents crucial therapeutic measures

More trials are needed to validate efficient drugs

REFERENCESWorld Gastroenterology Organisation Global Guidelines Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis June 2012

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 June 2012

AASLD PRACTICE GUIDELINE

The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association 2012

THANK YOU