الله مسب نمحرلا میحرلا · marker of hepatic appoptosis •Polypeptide specific antigen: released during appoptosis •Endothelin 1: is a mediator of fibrosis •Adiponectin:

بسم هللا الرحمن

الرحیم

Metaboloic syndrome GI and hepatobiliary system

• Components of MS:

• DM

• Hyperlipidemia

• Hypertension

• Obesity

• CVD

Metaboloic syndrome and GI and hepatobiliary system • GI

• Hepatobiliary


– Cancers: colon, Gall bladder, pancreas….

– Microbiota

• Hepatobiliary


– Cancers: colon, Gall bladder, pancreas….

– Microbiota

• Hepatobiliary

– Biliary

• Gallstone

• Gallbladder cancer


– Cancers: colon, Gall bladder,….

– Microbiota

• Hepatobiliary

– Biliary

• Gallstone


– Hepatic

• NAFLD


– Cancers: colon, Gall bladder,….

– Microbiota

• Hepatobiliary

– Biliary

• Gallstone


– Hepatic

• NAFLD

• HCC

• …..

Non-alcoholic fatty liver disease the hepatic

consequence of the metabolic syndrome

• NAFLD

–Definition: non alcoholic fatty liver disease

–Classification:

• NAFL

• NASH (nonalcoholc steatohepatitis)

• NAFLD

– Natural course

• NAFL NASH Fibrosis Cirrhosis HCC

• 70% of cryptogenic cirrhosis pts had risk factors of NAFLD.

• In one metaanalysis during a few years F/U – 36% increased inflammatory scores

– 46% stable

– 21% decreased inflammatory scores

Epidemiology

• The prevalence of NAFLD has been increasing along with the rise in obesity since the term non-alcoholic steatohepatitis (NASH) was coined by Ludwig in 1980.

• Patients with NASH are more likely to have the metabolic syndrome than are those with mere steatosis.

Epidemiology

• The estimated prevalence in the general population depends on the type of screening test and ranges from 2.8% to 46% for NAFLD and for NASH 1% to 4% in unselected populations worldwide

• Ethnic variation in the prevalence of NAFLD/NASH has been described; several studies have indicated less common prevalence in African Americans.

Epidemiology

• NAFLD is one of the most common liver disorders in industrialized countries, with type 2 diabetes, obesity, hyperlipidemia, and cardiovascular disease being the most frequently evaluated and cited risk factors for the presence of NAFLD and accelerated disease.

Epidemiology

• NAFLD is one of the most common liver disorders in industrialized countries, with type 2 diabetes, obesity, hyperlipidemia, and cardiovascular disease being the most frequently evaluated and cited risk factors for the presence of NAFLD and accelerated disease.

• The prevalence of NAFLD in Iran was 15.3% (Shiraz) to 43.8% (Amol)

Non-alcoholic fatty liver disease prevalence among school-aged children and adolescents in Iran

• 966 children aged 7–18 years in Iran by a cross-sectional survey in 2007.

• Fatty liver was diagnosed by ultrasound in 7.1% of children. The prevalence of elevated alanine aminotransferase (ALT) was 1.8%. NAFLD was significantly more common in the older group.

Alavian SM, et al. . Non-alcoholic fatty liver disease prevalence among school-aged children and adolescents in Iran and its association with biochemical and anthropometric measures. Liver Int. 2009 Feb;29(2):159-63.

Risk Score Model for Predicting Sonographic Non-alcoholic Fatty Liver Disease in Children and

Adolescents • Cross-sectional study was conducted among 962

participants aged 6-18 years in Isfahan, Iran.

• The sonographic findings of 16.8% of participants were compatible with NAFLD. Age, sex, body mass index, waist circumference and serum triglycerides level were diagnosed as factors associated with NAFLD.

Hosseini SM, et al. Risk Score Model for Predicting Sonographic Non-alcoholic Fatty Liver

Disease in Children and Adolescents. Iran J Pediatr. 2011 21(2):181-7.

• In an autopsy study performed on 896 postmortem subjects at the Forensic Medicine Center in Tehran who died of acute incidents not related to hepatic disorders, 2.1% of cases were found to have NASH upon histological evaluation.

Sotoudehmanesh R,, et al. Silent liver diseases in autopsies from forensic medicine of Tehran. Arch Iran Med. 2006 Oct;9(4):324-8.

• A recent review by Tilg and Moschen proposed the 'multiple parallel hits' hypothesis, where inflammation arises as a consequence of many parallel hits originating from visceral adipose tissue and/or gut; according to this hypothesis, gut-derived bacterial byproducts, cytokine and adipokine signaling, endoplasmic reticulum (ER) stress and innate immunity emerge as key factors in NASH pathogenesis.

• Currently, it is widely accepted that lipopolysaccharide (LPS), a gut bacteria-derived endotoxin, is important for the development and progression of ASH and NASH through TLR-4 activation and induction of Kupffer cell activity.

Signs and symptoms • Asymptomatic in majority of cases

• Fatigue (not correlated with liver injury severity)

• RUQ pain or discomfort

• Hepatomegaly (50%)

• Cirrhosis and portal hypertension

• Obesity

• Hypertension

• Cardiovascular or cerebrovascular diseases

• PCOD

• Lipodystrophy (in non obese)

Diagnosis • NAFLD is a diagnosis of exclusion

Imaging evidences of liver steatosis with eclusion of

-Alcoholic

-Drug induced (tamoxifen, amiodarone)

-Viral

-Autoimmune

-Metabolic (Wilson and Hemochromatosis)

Steatohepatitis

• The most challenging DDX is alcoholic hepatitis

• The histologic picture of both conditions is similar

• Consumption of alcohol less than 10 g/d in women and 20 g/d in men

Laboratory Investigations

• ~ 80% in normal range

• None of the currently used tests are specific for the diagnosis of NAFLD

• Aminotransferase elevation (< 4 times ULN)

• It does not correlate with the severity of steatosis or fibrosis

• AST/ALT ratio (AAR) is usually <1, and > 1 suggesting cirrhosis

• Higher AST , ALT levels and AAR are associated with NASH

• The pattern of aminotrasferase elevation do not provide a distinction between simple fatty liver and NASH.

• The differentiation between these conditions can be made by a histological approach.

• The amount of liver fat can not be assessed using liver function tests

• The degree of fat infiltration might be diagnosed using a variety of imaging modalities

• Serum Ferritin elevation (20-50%) • Indicates liver fibrosis not iron overload • Increased transferrin saturation (5-10%)

• Hyperuricemia is associated with cirrhosis related

deaths or hospitalizations

• Alkaline phosphatase and GGT might be increased in advanced disease and might indicate the increased mortality

• Autoantibodies might be present at low titers especially in advanced disease

Imaging studies

Ultrasonography

- Safe, easy to perform, and acceptable

- First line imaging

- Hyperechogenic liver parenchyma in contrast to kidney or spleen

- Hepato-renal index

- Spleen longitudinal diameter (might differentiate between

NASH and simple fatty liver)

• Sensitivity is dependent on the degree of steatosis (decreased in morbid obesity)

• Specificity is high (~ 90%)

• Can not differentiate steatosis from fibrosis

• Contrast enhanced ultrasonography:

- The role of hepatic vein transit times (HVTT) using a micro bubble contrast agent as a tracer

- Decrease signal intensity in NASH compared with simple fatty liver due to reduced uptake of levovist mediated by cell injury

Normal appearance of the liver at US. The

echogenicity of the liver is equal to or slightly

Greater than that of the renal cortex (rc).

Normal appearance of the liver at unenhanced CT. The attenuation of the liver (66 HU) is slightly higher than that of the spleen (56 HU), and intrahepatic vessels (v) appear hypoattenuated in Comparison with the liver.

. Normal appearance of the liver at MR imaging. Axial

opposed-phase (a) and axial in-phase (b) T1- weighted GRE images

show similar signal intensity of the liver parenchyma.

Accuracy for Detection and Grading of Fat Deposition

Reported sensitivities and specificities for detection of fatty liver deposition are

60%–100% and 77%–95% for US,

43%–95% and 90% for unenhanced CT,

and 81% and 100% for chemical shift GRE MR

imaging.

Accuracy for Detection and Grading of Fat Deposition

A US-, CT-, and MR imaging–based diagnosis of fatty liver may be unreliable in the presence of a liver fat content of less than 30% in wet weight, although MR techniques that are currently in developmental stages are likely to be reliable even in the presence of a low liver fat content.

A few research groups have developed CT and MR

techniques that show promise for use in the quantitative grading of liver fat content

• Non of the imaging modalities are able to differentiate NASH from simple fatty liver disease

• Liver biopsy is the gold standard? for the definite assessment of steatosis, necroinflammation, and fibrosis

Liver biopsy

limitations:

• Invasive

• Risk of complications

• Sampling error

• Interobserver variability

• Cost

Biomarkers for assessment of steatohepatitis and fibrosis

• C reactive protein: independent risk factor for the progression of NAFLD

• Plasma Pentraxin 3: risk factor for the progression of NAFLD

• IL6: indicate inflammmatory activity and the degree of fibrosis

• TNF α: risk factor for the progression of NAFLD

• Cytokeratin 18: marker of hepatic appoptosis

• Polypeptide specific antigen: released during appoptosis

• Endothelin 1: is a mediator of fibrosis

• Adiponectin: is lower in NASH

• Oxidative stress biomarkers ? (superoxide desmutase, glutathione peroxidase, Thioredoxin)

• Hyaluronic acid ? • Type 4 collagen 7S domain ? • Laminin ?

• Presence of DM (type2), obesity, hypertension, and aminotrasferase elevation are markers of fibrosis

• The utility of these tests are limited in cases with advanced fibrosis

• The best result for non invasive staging will be achieved by combining a clinical/biochemical scoring system with elastography

Fibroscan • Transient elastography that evaluates liver

stiffness using pulse-echo ultrasound

• Non invasive

• More sensitive than serologic markers

• Evaluates a larger part of liver (500 to 1000 times than Bx)

• Might be unreliable in obese

• Could define fat content of liver

• In patients with normal ALT and liver stiffness value <6.0 kPa, no treatment is required, whereas those with liver stiffness values >9.0 kPa should be considered for treatment.

• In patients with ALT 1-5x ULN, those patients with liver stiffness value <7.5 kPa can be observed, whereas those with value >12.0kPa should be considered for treatment.

• In patients with liver stiffness values outside these criteria, liver biopsy should be considered.

• In early results of Mashhad study for NAFLD fibroscan was the most sensitive test for NAFLD Dx.

Practical recommendations for lifestyle modification

• Exercise goal is 30–45 minutes of activities that increase heart rate at least three times weekly

• Walking is a good start for people completely sedentary, but the goal is to move onto aerobic activities as fitness improves

• Vary exercise activities over time

• Seek a trainer to guide develop and plan to maintain consistency

• Do not think of weight loss as the goal of exercise; the goal of exercise is to change the body’s metabolism and improve the sense of well-being

Practical recommendations for lifestyle modification

• Limit ‘‘screen time’’ in front of televisions, computers, and video games

• Focus on healthy eating, not dieting

• Eat a protein-containing breakfast daily (eg, meat, cheese, eggs, yoghurt)

• Avoid fasting

• Eliminate sugar-sweetened beverages (sodas, sweetened tea, and so forth)

• Avoid trans-fats, including foods labeled as trans-fat free but containing hydrogenated or partially hydrogenated vegetable oil

LIVER TRANSPLANTATION

• Decompensated liver disease in the setting of NASH cirrhosis is a relatively uncommon

• finding compared with other common causes of liver disease such as HCV, but

• the sheer scale of the obesity epidemic in the United States has lead to predictions

• that NASH cirrhosis will become the leading indication for OLT in the next decade

Take summary message

• NAFLD is very common



• Its prevalence is progressive




• The disease course is progressive also





• It is mostly preventable with low cost





• It is mostly preventable with low cost

• Otherwise might be the most important medical and health issue in near future

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Documents

الله مسب نمحرلا میحرلا · marker of hepatic appoptosis •Polypeptide specific antigen: released during appoptosis •Endothelin 1: is a mediator of fibrosis •Adiponectin: