Non alcoholic fatty liver disease(NAFLD)

Diagnosis and evaluationDiagnosis and evaluation

Raika Jamali M.D.Gastroenterologist and hepatologist

Tehran University of Medical Sciences

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 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.

• The estimated prevalence in the general population depends on the type of screening test and ranges from 2.8% to 46% 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.

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.

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.

Role of Immune Response in NASH

• 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.

KCs

• KCs represent the largest group of tissue resident macrophages in the body.

• They are able to release pro-inflammatory cytokines such as IL-1, IL-6, and TNFɑ which promote the infiltration of neutrophilic granulocytes to eliminate bacteria.

• KCs also produce IL-12 and IL-18 which activate NK cells to produce anti-viral IFN γ.

• However, following initial activation to produce pro-inflammatory cytokines, KCs release IL-10 which down-regulates the production of TNFɑ , IL-6 and other cytokines and thereby probably contributes to the intrahepatic cell populations capability to induce tolerance.

Hepatic stellate cells

• HSCs, well described for their participation in hepatic fibrosis and storage of vitamin A, have been shown recently to also function as APCs .

• They are able to present lipid antigens to CD1d-restricted T cells, i.e. to NKT cells.

• They are able to present protein antigens to conventional CD4+ or CD8+ T cells

• Indeed, CD4 T cells can be converted to induced regulatory T cells (iTregs) by vitamin A derived retinoic acid and/or TGFβ .

• Moreover, activated HSCs express the negative co-stimulator PD-L1 .

NAFLD pathogenesis in ob/ob mice

Leptin deficiency Kupffer cell inhibited activation of

dysfunction Hepatic stellate cells

Hepatic NKT Increased adipokines cell depletion (resistin,adiponectin)

inhibited liver fibrosis Th-1 polarization Despite Liver injury

increased ROS

Hepatocyte oxidative stress

• 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.

• Oxidative stress may directly activate an immune response and, subsequently, drive further inflammation, or may be the result of inflammation.

• Hepatic oxidative stress, lipid peroxidation and ER stress can directly activate the inhibitor of NF-κB kinase or JNK to activate transcription of proinflammatory cytokines.

• The best examples of pattern-recognition receptors include a group of Toll-like receptors (TLRs), which recognizes pathogen-associated molecular patterns to determine the presence of pathogens.

• Once pathogens are identified, TLRs then induce multiple signaling pathways that regulate the expression of proinflammatory cytokines and chemokines to mount protective responses against invading pathogens.

• Experimental and clinical data have demonstrated that levels of circulating and hepatic LPS are elevated in both ASH and NASH.

• Increased LPS levels in NASH are likely owing to small intestinal bacterial overgrowth and alterations of the intestinal barrier.

• Reportedly, Szabo’s group has determined that TLR-2, which recognizes lipoproteins and peptidoglycans from gram-positive bacteria, plays a protective role in NASH, but has no role in the pathogenesis of ASH.

• Natural killer (NK) T cells are regulatory T lymphocytes that are preactivated in situ by endogenous glycolipids, and are therefore considered to be innate immune effectors.

• NKT cells are present in normal liver and are relatively depleted in steatosis.

• Initial evidence points towards their fourfold increase in NASH-related cirrhosis, but there are no data on their numbers in early-stage NASH.

• The adaptive immune response in NAFLD involves CD4+ T-helper cells, and although NASH is not classically considered a Th1-polarized disease, recent data suggest that its pathogenesis may be influenced by an imbalance between a relative excess of proinflammatory Th1 cytokines (i.e., IFN-γ) and a deficiency in anti-inflammatory IL-4 and IL-10 cytokines.

•

• Emerging evidence also points towards a functional role of Th17-mediated T-cell responses in the pathogenesis of NASH.

• Th17 cells are a recently described subset of CD4+ T-helper cells producing the cytokine IL-17. IL-17 can induce the expression of neutrophil-attracting chemokines in epithelial and endothelial cells, but it can also by itself mobilize and activate neutrophils.

• In fatty liver, the characteristic perivenular infiltration of both neutrophils and lymphocytes suggests enhanced recruitment via their two major receptors CXCR1 and CXCR2.

• Circulating, as well as liver and adipose tissue levels of TNF-α, are increased in animal models of obesity.

• This is also true in humans, where TNF-α levels correlate with the degree of insulin resistance.

• Furthermore, in humans, acute infusion of TNF-α inhibits insulin-stimulated glucose disposal,and certain TNF-α polymorphisms are associated with susceptibility to insulin resistance and NAFLD,

supporting the importance of this cytokine in the interaction among inflammation, insulin signaling, and fat accumulation.

Key points

• Serum levels of TNF-α correlate with NASH activity however, levels of IL-6 do not.

• Low serum levels of adiponectin have been strongly correlated with NASH.

• The use of pentoxifylline, a known TNF-α inhibitor, has revealed mixed results.

• In a small, open-labeled pilot study evaluating the use of pentoxifylline (1,600 mg/day) in patients with biopsy-proven NASH, improvement was documented in serum transaminase levels over a 12-month period.

• In 2007, Satapathy et al. reassessed the use of pentoxifylline in patients with NASH, but at a dose of 1,200 mg/day over 12 months.

• At the end of the study, serum transaminases and liver histology (including signs of liver injury, inflammation, and fibrosis) were significantly improved.[64]

• Pentoxifylline is a relatively weak and nonspecific TNF-α inhibitor, and thus the use of more selective TNF-α blockers, such as infliximab and adalimumab, could potentially be more effective in the treatment of NAFLD.

• Inhibitors targeted at IL-6 may be another potential target for preventing progression of steatohepatitis.

• A humanized IL-6 receptor antibody, tocilizumab, has been developed to inhibit IL-6 binding to its receptor.

• Tocilizumab has been investigated in clinical trials as a treatment for rheumatoid arthritis.

• In a multicenter, randomized controlled trial in which patients were treated with tocilizumab or placebo over 3 months, tocilizumab significantly reduced disease activity in rheumatoid arthritis patients.[65, 66]

• It is possible that this drug could be efficacious in NAFLD as well.

• In addition, as it has been established that hypoadiponectemia is associated with disease progression, administration of adiponectin could potentially prevent development of severe steatohepatitis in patients with documented steatosis and mild steatohepatitis.

• No human studies of adiponectin therapy have been performed to date.

• As our understanding of the pathophysiology of NASH evolves, therapeutic targets for the treatment of NASH emerge.

• One such potential target is NF-κB Selective targeting of NF-κB signaling of inflammatory cells may be crucial in therapy design, as NF-κB may also act as a hepatocellular survival factor, and its inhibition may therefore lead to enhanced apoptosis and compensatory hepatocyte proliferation, favoring HCC development.

• A second selective target for NASH may be modulation of the JNK pathway. Selective blockade of JNK1 may be associated with improved hepatic steatosis, insulin resistance and inflammation; however, blockade of JNK2 may exacerbate hepatocellular injury.

• Alternately, modulation of the gut flora or inflammatory cytokines may prove beneficial;[79] however, this has not been reproduced in human studies. Further work is needed to evaluate these and other potential therapeutic targets for NASH.

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• OSA• Lipodystrophy (in non obese)

Diagnosis• NAFLD is a diagnosis of exclusion

-Alcoholic Hepatitis-Drug induced Hepatitis (tamoxifen, amiodarone)-Viral Hepatitis-Autoimmune Hepatitis-Metabolic (Wilson and Hemochromatosis)

• 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

• NAFLD is considered the hepatic manifestation of insulin resistance (metabolic) syndrome

• Might be discovered incidentally in a check up

• laboratory investigations alone have limitations for the diagnosis of NAFLD

• Combination of imaging studies is necessary for the estimation of liver steatosis

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) > 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

• Hyperbilirubinemia, hypoalbominemia and abnormal prothrombin time are present in cirrhosis

• Hyperglycemia, hypertriglyceridemia, hypercholestrolemia are related to metabolic syndrome

• HOMA (FIL X FPG / 22.5) is an estimate of insulin resistance

• A correlation between HOMA and hepatic steatosis is demonstrated

• Decreased apolipoprotein B is a rare cause of familial NAFLD (with normal LDL and HDL)

• 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

UltrasonographyUltrasonography

- 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

Doppler ultrasonography

• Associated with hepatic parenchyma perfusion abnormality

• Hepatic vein Doppler pattern

• Doppler perfusion index (DPI): a ratio between hepatic arterial blood flow and total liver blood flow

ImagingPatterns OF Fatty Liver

Fatty liver is a common abnormality among patients undergoing cross-sectional imaging of the abdomen. The image-based diagnosis of fatty liver usually is straightforward, but fat accumulation may be manifested with unusual structural patterns that mimic neoplastic, inflammatory, or vascular conditions. On these occasions, the imaging appearance of the liver may cause diagnostic confusion and lead to unnecessary diagnostic tests and invasive procedures. To avoid such mistakes, radiologists should be aware of the many imaging manifestations of fatty liver.

• This Presentation provides a review of the imaging appearances of fat accumulation in the liver.

• Herein we describe the different structural patterns of fat accumulation that may be seen at ultrasonography (US), computed tomography (CT), and magnetic resonance (MR) imaging.

• We also discuss diagnostic pitfalls and explain how to distinguish between fat deposition and more ominous conditions of the liver.

Imaging-basedDiagnosis of Fatty Liver

Liver biopsy and histologic analysis is consideredthe diagnostic reference standard for theAssessment of fatty liver. However, fatty liver also can be diagnosed withthe use of cross sectional imaging

Diagnosis at USThe echogenicity of the normal liver equals or minimally exceeds that of the renal cortex or spleen.

Intrahepatic vessels are sharply demarcated, and posterior aspect of the liver are well depicted .

Fatty liver may be diagnosed if liver echogenicity exceeds that ofrenal cortex and spleen and there is attenuation of the ultrasoundwave, loss of definition of the diaphragm, and poor delineation ofthe intrahepatic architecture.

To avoid false-positive interpretations, fatty liver should not beconsidered present if only one or two of these criteria are fulfilled.

Normal appearance of the liver at US. Theechogenicity of the liver is equal to or slightlyGreater than that of the renal cortex (rc).

Diagnosis at CTAt unenhanced CT, the normal liver has slightly greater attenuation than the spleenand blood, and intrahepatic vessels are visible as relatively hypoattenuated structures.

Fatty liver can be diagnosed if the attenuation of the liver is at least 10 HU less than that ofthe spleen or if the attenuation of the liver is less than 40 HU.

In severe cases of fatty liver, intrahepatic vessels may appear hyperattenuated relative tothe fat containing liver tissue. Other CT criteria have been advocated.

At contrast material–enhanced CT, the comparison of liver and spleen attenuation values isnot as reliable for the diagnosis of fatty liver, because differences between the appearanceof the liver and that of the spleen depend on timing and technique and because there isoverlap between normal and abnormal attenuation value Ranges .

Fatty liver can be diagnosed at contrast-enhanced CT if absolute attenuation is less than 40HU, but this threshold has limited sensitivity.

Normal appearanceof the liver at unenhancedCT. The attenuation of theliver (66 HU) is slightlyhigher than that of thespleen (56 HU), andintrahepatic vessels (v)appear hypoattenuated inComparison with the liver.

Diagnosis at MR ImagingChemical shift gradient-echo (GRE) imaging with in-phase and opposed-phase acquisitions is the mostwidely used MR imaging technique for the assessment of fatty liver. The signal intensity of the normal liver parenchyma is similar on inphase and opposed-phase images ). Fatty liver may be present if there is a signal intensity loss on opposed-phase images in comparison with inPhase images, and the amount of hepatic fat present can be quantified by assessing the degree of signalintensity loss.Fat deposition also can be diagnosed by observing the signal intensity loss of liver on MR images after theApplication of chemical fat saturation sequences, but this method is less sensitive than is chemical shift GREimaging for the Detection of fatty liver.On in-phase GRE images or T1- or T2- weighted echo-train spin-echo images, higher than normal liver signalintensity is suggestive of fat deposition, but this finding is neither sensitive nor specific unless themeasurement technique is correctly calibrated.Proton MR spectroscopy is the most accurate noninvasive method for the assessment of fatty liver.However, this method does not generate anatomic images.

. Normal appearance of the liver at MR imaging. Axialopposed-phase (a) and axial in-phase (b) T1- weighted GRE

imagesshow similar signal intensity of the liver parenchyma.

Accuracy for Detectionand Grading of Fat Deposition

Reported sensitivities and specificities for detection of fatty liverDeposition are 60%–100% and 77%–95% for US, 43%–95% and 90%for unenhanced CT, and 81% and 100% for chemical shift GRE MRimaging.

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

A few research groups have developed CT and MR techniques thatshow promise for use in the quantitative grading of liver fat content

Patterns of Fat Deposition

Diffuse Deposition

Diffuse fat deposition in the liver is the mostFrequently encountered pattern.

Liver Involvement usually is homogeneous, andThe image interpretation is straightforward ifthe rules specified earlier are applied.

Diffuse fat accumulation in the liver at US.The echogenicity of the liver is greater than that of therenal cortex (rc). Intrahepatic vessels are not well depicted.The ultrasound beam is attenuated posteriorly,and the diaphragm is poorly delineated.

Diffuse fat accumulation in the liver at unenhancedCT. The attenuation of the liver (15 HU) ismarkedly lower than that of the spleen (40 HU). Intrahepaticvessels (v) also appear hyperattenuated in comparisonwith the liver.

Diffuse fat accumulation in the liver at MR imaging.Axial T1-weighted GRE images show a markeddecrease in the signal intensity of the liver on the opposedphase image (a), compared with that on the in-phase image (b).

Focal Deposition and Focal Sparing

Slightly less common patterns are focal fat deposition and diffuse fat deposition with focal sparing.

In these patterns, focal fat deposition or focal fat sparing characteristically occurs in specific areas (eg, adjacent to thefalciform ligament or ligamentum venosum, in the porta hepatis, and in the gallbladder fossa) ; this distribution is notyet fully understood but has been attributed to variant venous circulation, such as anomalous gastric venous drainage.

Focal fat deposition adjacent to insulinoma metastases also has been reported and is thought to be due to local insulineffects on hepatocyte triglyceride Synthesis and accumulation.

The diagnosis of focal fat deposition and focal sparing is more difficult than that of homogeneously diffuse fatdeposition because imaging findings may resemble mass lesions.

Imaging findings suggestive of fatty pseudolesions rather than true masses include the following: fat content, locationin areas characteristic of fat deposition or sparing, absence of a mass effect on vessels and other liver structures, ageographic configuration rather than a round or oval shape, poorly delineated margins, and contrast enhancement thatis similar to or less than that of the normal liver Involved areas usually are relatively small, but occasionally there maybe confluent heterogeneous regions of focal deposition and sparing that span large areas of the liver.

Focal fat accumulation in the liver at US.Transverse image shows, adjacent to the left portalvein, a geographically shaped area of high echogenicitythat represents accumulation of fat (f) in the falciformligament, with posterior acoustic attenuation(arrows).

Focal fat accumulation in the liver at CT.Axial contrast-enhanced image obtained during theportal venous phase shows hypoattenuated regions offocal fat accumulation adjacent to the falciform andvenous ligaments and in the porta hepatis, with no evidenceof a mass effect.

. Diffuse fat accumulation with focal sparing at US and CT. Transverse US image (a) and axial unenhanced

CT image (b) obtained at comparable levels show high echogenicity and hypoattenuation, respectively,

features indicative of a diffuse accumulation of fat in the liver. Focal sparing (fs) is manifested as a geographically

shaped area with relative hypoechogenicity in a and hyperattenuation in b. The focal fatty pseudolesion

exerts no mass effect on the adjacent vessel (v in b).

Multifocal DepositionAn uncommon pattern is multifocal fat deposition.In this pattern, multiple fat foci are scattered in atypical locations throughout the liver. The foci may be round or oval and closely mimic true nodules. Correct diagnosis is difficult, especially in patients with a known malignancy, and requires theDetection of microscopic fat within the lesion. For this purpose, chemical shift GRE imaging is more reliable than CT or US. Other clues indicative of multifocal fat deposition are lack of a mass effect, stability in sizeover time, and contrast enhancement similar to or less than that in the surrounding liverparenchyma.In some cases, the foci of fat deposition have a confluent pattern. Multifocal fat deposition may be observed within regenerative nodules in some cirrhoticpatients; in these cases, the foci of fat accumulation correspond to the fat-containingregenerative nodules. Except for fat deposition in regenerative cirrhotic nodules, the pathogenesis of multifocal fatDeposition In the liver is unknown.

. Multifocal fat accumulation in the liver at CT and MR imaging in a 48-year-old woman with breast

cancer. (a) Unenhanced CT image shows multiple hypoattenuated 1-cm nodules (arrows). (b, c) T1-weighted GRE

MR images show nodules (arrows) with a signal intensity slightly higher than that of the normal liver parenchyma on

the in-phase image (b) but with a signal intensity loss on the opposed-phase image (c). The nodules were mistaken

for metastases at CT but were correctly diagnosed as multifocal fat accumulation in the liver on the basis of MR findings.

Confluent foci of fat accumulation in the liver at MR imaging. Axial T1-weighted MR images show a

large irregular region with a loss of signal intensity on the opposed-phase image (contour outline in b), compared

with the signal intensity on the in-phase image (a). Note the

absence of a mass effect.

Perivascular DepositionA perivascular pattern of fat deposition in the liver has been describedpreviously. This pattern is characterized by halos of fat that surround the hepaticveins, the portal veins, or both hepatic and portal veins.The configuration is tramlike or tubular for vessels with a course inthe imaging plane and ringlike or round for vessels with a courseperpendicular to the imaging plane. An unequivocal signal intensity loss on opposed- phase images incomparison with that on in-phase images and the lack of a mass effectOn the surrounded vessels are indicative of the diagnosis.

Perivenous fat accumulation in the liver at CT and MR imaging. (a, b) Axialunenhanced CT image (a) and axial contrast-enhanced equilibrium phase CT image (b) showhalos of hypoattenuation (40 HU) that closely surround the hepatic veins (arrows) and that aremore visible on b than on a. The rest of the liver has normal attenuation (63 HU at unenhancedCT). (c, d) Coronal T1-weighted GRE MR images. Opposed-phase image (c) shows an unequivocalsignal intensity loss in the regions that surround the hepatic veins (arrows), which appearslightly hyperintense on the in-phase image (arrows in d). This feature helps confirm thepresence of fat accumulation.The signal intensity of the normal liver parenchyma (*) in c differs from that in d because ofdifferent window width and level settings.

. Periportal fat accumulation in a patient with a chronic hepatitis Binfection. Axial unenhanced (a) and contrast-enhanced (b) CT images fromthe late portal venous phase show no morphologic evidence of cirrhosis.Partially confluent halos with hypoattenuation (40 HU at unenhanced CT)indicative of fat deposition closely surround the portal venous segments(arrows in b), with regions of less marked fat deposition bordering the

Periportal halos and in the periphery of the liver.

Subcapsular Deposition

In patients with renal failure and insulin-dependent diabetes, insulin may beadded to the peritoneal dialysate during kidney dialysis. This route of insulin administration exposes subcapsular hepatocytes to ahigher concentration of insulin than that to which the remainder of the liveris exposed.Since insulin promotes the esterification of free fatty acids into triglycerides,the peritoneal administration of insulin results in a subcapsular pattern of fatdeposition, which may be manifested as discrete fat nodules or a confluentPeripheral region of fat. A review of the patient’s clinical history in conjunction with the imagingfindings should facilitate correct diagnosis.

Differential Diagnosis

The diagnosis of diffuse fat deposition in theLiver tends to be straightforward. The differential diagnosis of other patterns of fatdeposition is discussed below.

Primary Lesions andHypervascular Metastases

In general, the differentiation of focal or multifocal fat accumulations from primaryhepatic lesions (eg, hepatocellular carcinoma, hepatic adenoma, and focal nodularhyperplasia) or from hypervascular metastases in the liver is not problematic becausethese lesions exert a mass effect, tend to show vivid or heterogeneous enhancementafter contrast agent administration, and may contain areas of necrosis or hemorrhage

Infiltrative hepatocellular carcinoma is a notable exception; on CT images, this tumormay exert a minimal mass effect, show little evidence of necrosis, show the samedegree of enhancement as the normal liver parenchyma, and closely resemble heterogeneous fat deposition.In our experience, correct diagnosis is usually possible with MR imaging, but theCorrelation of imaging findings with serum biomarkers may be helpful.

. Differentiation of adenoma from fatty deposition in the liver in a woman with a long history of oral contraceptive

use. (a, b) Axial opposed-phase (a) and in-phase (b) T1-weighted GRE images show diffuse fat deposition

in the liver, indicated by areas with a signal intensity loss on a in comparison with b. Two round masses in the

left lobe of the liver (arrows in a) resemble nodular areas of sparing. (c, d) Three-dimensional T1-weighted GRE

images obtained before (c) and during (d) the hepatic arterial phase show enhancement of the masses (arrows in c

and d) after the administration of a gadolinium-based contrast agent. The rounded shape of the lesions, as well as

their location, which is atypical for regions of fatty liver sparing, are important clues suggestive of tumors. The two

masses remained stable in size for several years and most likely are adenomas.

Differentiation of hepatocellular carcinoma from fatty deposition in the liver. Axial unenhanced (a) and

axial contrast-enhanced (b) CT images obtained during the portal venous phase show a nodular liver contour suggestive

of cirrhosis, as well as large gastric varices (arrowheads in b). In b, the right lobe of the liver appears hypoattenuated

in comparison with the left lobe, a finding that could be misinterpreted as evidence of regional fatty liver deposition;

however, the mass effect with bulging of the anterolateral border of the right liver lobe (arrow), the mosaic

enhancement pattern, and the thrombus (t) in the left main portal vein are strongly suggestive of an infiltrative malignancy.

This is a case of infiltrative hepatocellular carcinoma.

. Differentiation of metastases from fatty liver deposition in a woman undergoing chemotherapy for

breast cancer. Axial unenhanced (a, c) and contrast-enhanced (b, d) CT images (c and d at a higher level than a and

b) show diffuse fatty deposition in the liver and a geographic pseudolesion at the porta hepatis (arrows in a and b), a

finding that represents focal sparing. Multiple round lesions (arrows in c and d), which are more vividly enhanced

than the liver parenchyma, represent metastases. If unenhanced CT had not been performed, the region of focal sparing

on the contrast-enhanced images may have been mistaken for an enhanced hypervascular tumor.

HypovascularMetastases and Lymphoma

The differentiation of focal or multifocal fatDeposition from hypovascular metastases andLymphoma in the liver may be difficult. However, the clinical manifestations and imagingfeatures such as lesion morphology, location, andMicroscopic fat content usually permit a correctdiagnosis.Chemical shift GRE imaging may be necessary toassess the amount of intralesional fat.

Perfusion Anomalies

Perfusion anomalies may resemble fatDeposition morphologically but are visible onlyduring the arterial and portal venous phasesafter contrast agent administration. They are not detectable on unenhanced imagesor equilibrium phase images.

. Differentiation of superior vena cava syndrome from fatty liver deposition. Axial contrast-enhanced CT

images obtained during the arterial phase at the level of the liver (a) and the upper mediastinum (b) show a hyperattenuated

geographic pseudolesion (white arrow in a) in segment IV, at the anterior border of the liver, and obstruction

of the superior vena cava by a thoracic mass (arrow in b). With regard to morphologic features, the pseudolesion

resembles a focal area of fatty liver deposition or sparing, but its marked enhancement on early phase images helps

confirm that the lesion represents a perfusion abnormality—in this case, one associated with superior vena cava syndrome.

Note the large systemic collateral veins (arrowheads in a and b) and the collateral draining vessel in segment

IV (black arrow in a).

. Differentiation of hepatic venous congestion(nutmeg liver) from fatty liver deposition. Axialcontrast-enhanced CT image obtained at the level ofthe liver during the hepatic arterial phase shows

irregularareas with low attenuation in the nutmeg pattern,features that could be mistaken for multifocal or

geographicfatty liver deposition. However, this patternwas visible only on arterial phase images and early

portalvenous phase images and not on unenhanced imagesor images obtained in later phases. A pericardialeffusion also was present. Nutmeg liver is a perfusionabnormality that is related to hepatic venous

congestionfrom cardiac disease or other causes.

Differentiation of transient hepatic attenuationdifference from fatty liver deposition. Axial unenhancedCT image (a) and axial contrast-enhanced latearterial phase (b) and portal venous phase (c) CT imagesobtained at the same level in the liver. A wedgeshapedperipheral hyperattenuated pseudolesion (whitearrows in b) with straight borders appears on the arterialphase image but not in a or c. The wedgelike shape,straight borders, peripheral location, and transient enhancementof the lesion are suggestive of a transient differencein hepatic attenuation rather than a mass or a fatdeposition abnormality. Note the arterialized flow in afeeding branch of the portal vein (black arrow in b), afinding that represents an iatrogenic postbiopsy arteriovenousfistula.

Periportal Abnormalities

The US- and CT-based differential diagnosis of periportal fat depositionis broad and includes edema, inflammation, hemorrhage, andLymphatic dilatation. Edema, inflammation, and lymphatic dilatation tend to affect thePortal triads symmetrically. Hemorrhage characteristically involves the portal triads

asymmetricallyand may be associated with laceration or other signs of injury. None of these entities are associated with microscopic fat. Thus, if chemical shift imaging is performed, a signal intensity loss ofPerivascular tissue on opposed-phase images permits the correctdiagnosis of fat deposition.

. Differentiation of periportal inflammation from fatty liver deposition. Axial contrast-enhanced CT images

obtained during the portal venous phase (a) and the equilibrium phase (b). The hypoattenuated halos (arrows)

that surround the portal venous tracts in a could be misinterpreted as perivascular fat accumulation, but they retain

contrast material and appear hyperattenuated in b. Retention of contrast material on delayed images is suggestive of

periportal inflammation with transcapillary leakage of the contrast agent into inflamed periportal tissue; perivascular

fat deposition would not be expected to retain contrast material. The attenuation of periportal halos should be measured

on unenhanced or delayed phase images, if available, to help differentiate periportal fat deposition from edema

or inflammation.

Pitfalls

Fat-containing Primary Tumors

Hepatic adenomas, hepatocellular carcinomas,and, rarely, focal nodular hyperplasias may havemicroscopic fat content. Hence, a finding of intralesional fat does not helpexclude these entities, and clinical findings as wellas imaging features such as morphologic structure,mass effect, and enhancement characteristics mustBe considered .

Differentiation of a fat-containing tumor from fat deposition in the liver. Coronal T1-

weighted GRE MR images show a large mass (arrows) with lower signal intensity on the opposed-phase

image (a) than on the in-phase image (b), a feature indicative of fat. Vivid arterial enhancement (not

shown), the round rather than geographic shape of the lesion, and the mass effect are indicative of a

space-occupying lesion rather than fat deposition. The lesion was an exophytic hepatic adenoma.

Low-Attenuation Lesions

A threshold attenuation value of less than 40 HUin the liver at CT is not specific for a finding of fatdeposition. For example, ischemic or mucinousmetastases or abscesses may manifest lowAttenuation values. However, a review of the clinical manifestationsand laboratory findings in conjunction with otherCT features should lead to the correct diagnosis. Ifnecessary, chemical shift GRE imaging can beperformed.

. Differentiation of metastases from fat deposition in the liver. Axial portal venous phase contrast-enhanced

CT images at the level of the right hepatic vein (rhv) (a) and the pancreatic head (b) show innumerable hypoattenuated

lesions throughout the liver. Most of the lesions are round or oval, but the largest (m in b) has a geographic

configuration. Because of their low attenuation (40 HU), the lesions might be mistaken for multifocal fatdeposition; however, the mass effect of the lesions, which produces bulging of the liver surface (arrow)

and compressionof the right hepatic vein, as well as the multiplicity of lesions, their predominant round or oval shape,

the thrombus(t in b) in the superior mesenteric vein, and numerous heterogeneous lymph nodes (n in b), are

suggestive of malignancy.The lesions were identified as hematogenous metastases from pancreatic adenocarcinoma.

PET scanning using FDG is an imagingtechnique that displays glucose uptake bycells and therefore local metabolic activity.This metabolic activity can be estimatednoninvasively by a semiquantitative method,the standardized uptake value (SUV), bytaking into account factors such as the injectedactivity and patient weight (or lean bodymass) and the time after injection.

Regions of interest were placed on liver (large circles) and spleen (small circles) as well as on mediastinum

(not shown) on both CT (left) and PET (right) to calculate CT attenuation values and standardized uptake values,

respectively. In this case, mean hepatic attenuation was −13 HU

and mean splenic attenuation was 62 HU.

A–D, Estimated FF maps by using the four image analysis methods, E, multiecho MR spectra, and F–H, accompanying T2* maps in 18-year-old man with

biopsy-confirmed NAFLD. The ROIs (circles) on imaging and spectroscopic voxel have been colocalized. The spectroscopic FF was 24.2% in E. Imaging FFs were 21.8%

in A, 24.9% in B, 20.1% in C, and 24.9% in D. The estimated T2* values were 19.2 msec in F, 28.8 msec in G, and 24.7 msec in H. The triple-echo and multiinterference

methods show higher quantification accuracy than the dual-echo and multiecho methods. TEecho time.

• CT scan or MRI techniques are expensive• When the steatosis is focal• Evaluation of subcutaneous adipose tissue• A new MRI technique:

- Proton magnetic resonance spectroscopy (MRS) - Measures the fat proton fraction and hepatic

levels (HTGC)- HTGC > 5% is the diagnostic level for steatosis- More accurate than previous modalities for the

diagnosis of NAFLD

• 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 The gold standard for both diagnosis & prognosis Is not necessary in a typical patient Liver Bx is indicated in:

- High ferritin with HFE mutations- Positive autoantibodies- The use of medications associated with drug induced liver injury- Accurate staging of disease in patients with several risk factors

limitations:limitations:• Invasive• Risk of complications• Sampling error• Interobserver variability

NAFLD activity score (NAS)

Findings:Findings:• Macrovesicular steatosis• Lobular inflammation• Hepatocyte balooning• Perisinusoidal fibrosis__________________________________________________

• Histologic scoring system

• Score 5 or greater is consistent with NASH

• Score 2 or less is consistent with simple fatty liver

Biomarkers for assessment of Biomarkers for assessment of steatohepatitis and fibrosissteatohepatitis 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 ?

Panel of markers/Scoring systems Identification of steatosisIdentification of steatosis• “NAFLD liver fat score” includes:

- Presence of DM - Fasting serum insulin- AST- AST/ALT ratio

• “Fatty liver index” includes:- BMI- Waist circumference- Triglyceride- GGT

• “Visceral adiposity index” includes:- BMI- Waist circumference- Triglyceride- HDL

Panel of markers/Scoring systems Identification of inflammationIdentification of inflammation• “NASH test” includes:

- Total Bilirubin- GGT- α2 macroglobulin- Apolipoprotein A1- Haptoglobulin- ALT

• “HAIR test” includes:- Hypertension- ALT- Insulin resistance

• ‘Parkler model” includes:- age- gender- AST- BMI- AST/ALT ratio- Hyaluronic acid

Panel of markers/Scoring systemsIdentification of fibrosisIdentification of fibrosis

• AST/ALT ratio (AAR)• APRI test: uses platelet count and AST• “FIB 4 index” utilizes age, AST, ALT, and platelet count • “NAFLD fibrosis score” includes:

- BMI- Presence of DM- Albumin

• “Fibrotest” (BioPredictive) tacking into account:- GGT- Haptoglobulin- Bilirubin- Apolipoprotein A1- α2 macroglobulin

• “Fibro Spect” tacking into account:- Hyaluronic acid- Tissue inhibited matrix metalloproteinase- Inhibitor1- α2 macroglobulin

• 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• Main weakness is interference with by

steatosis with wave velocity• Might be unreliable in obese

• 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.

Acoustic radiation force impulse(ARFI)

• Sonoelastography that evaluates liver elasticity• Alternative to Fibroscan• Utilizes acoustic waves to interogate the

mechanical stiffness of liver• Can be used during standard US examination of

liver• Diagnosis of significant fibrosis__________________________________________• Another modality is magnetic resonance

elastography with higher diagnostic accuracy for fibrosis staging especially in obese

Total over night salivary caffeine assessment test

• A marker of systemic caffeine clearance

• It shows liver function in compensated cirrhosis

Dynamic breath tests• C-methacetin breath test (MBT) and C-octanoate breath test (OBT) evaluate

cytochrome P450 activity and mitochondrial dysfunction

• Both increase oxidative stress that is implicated in NASH

• MBT predict extent of liver fibrosis• OBT distinguish between simple fatty liver and

NASH

Non-alcoholic fatty liver disease

the hepatic consequence of the metabolic

syndrome

Causes of Non-Alcoholic Fatty Liver Disease

Several risk factors increase the likelihood of a person developing NAFLD.

Diabetes

Excess weight and obesity

High levels of fat in the blood (also known as hyperlipidemia)

Abdominal surgery

Taking certain medications such as corticosteroids, antiretrovirals, and immune-suppressing medications

Medical conditions: Rapid weight loss and malnutrition

There is evidence to suggest the presence of an association between metabolic syndrome( insulin resistance) and the development of NAFLD

What is metabolic syndrome?

coronary heart disease (CHD)

other forms of cardiovascular atherosclerotic diseases (CVD)

diabetes mellitus type 2 (DMT2).

stroke

Mets was originally defined as a cluster of interconnected factors that directly increase the risk of:

First termed syndrome X in 1988Insulin resistance syndrome; Syndrome x, dysmetabolic syndrome

Its main components are

• dyslipidemia

• elevation of arterial blood pressure (BP)

• dysregulated glucose homeostasis

• abdominal obesity

• insulin resistance (IR)• non-alcoholic fatty liver disease( Recently added to the

syndrome and make its definition even more complex.)

Adverse Health Effects of Metabolic Syndrome The two major metabolic syndrome health effects are: type 2 diabetes and cardiovascular disease

Common complications of metabolic syndrome include:

•Eye, kidney, cardiovascular, skin, and nerve problems. •Fatty liver - Disease . •Sleep apnea •Chronic kidney disease (CKD) •Polycystic ovarian syndrome (PCOS)

Recent research has also linked age-related memory loss (dementia) to metabolic syndrome as well as some types of cancer, such as colon cancer.

Epidemiology of Metabolic syndrome

Metabolic syndrome is increasing in prevalence, paralleling an increasing epidemic of obesity. .

The World Health Organization estimates 25% of adults world-wide are affected by metabolic syndrome

The prevalence of MetS varies and depends on:

the criteria used in different definition

the composition (sex, age, race and ethnicity) of the population studied

In the United States, more than one fourth of the population meets diagnostic criteria for Mets.

More than 45% of adult Americans over age 50 are affected . Approximately one fourth of the adult European population is estimated to have mets. similar prevalence in Latin America.

Asian countries(China, Japan, and Korea): range from 8-13% in men and 2-

18% in women . Iran:25-30%

Etiology and causes

Insulin resistance results from inherited and acquired influences

o Hereditary causes include :mutations of insulin receptor, glucose transporter, and signaling

proteins, although the common forms are largely unidentified.

o Acquired causes include physical inactivity, diet, medications, hyperglycemia (glucose toxicity), increased free fatty acids, and the aging process.

The exact cause of metabolic syndrome is not known.

Many features of the metabolic syndrome are associated with “insulin resistance.”

Metabolic Syndrome Risk Factors

Major Metabolic Syndrome Risk Factors

The major risks for metabolic syndrome include the key features of a

large waist line

abnormal cholesterol levels,

hypertension

high fasting blood glucose

Metabolic Syndrome Risk Factors

Non-Modifiable Metabolic Syndrome Risk Factors

Non-modifiable risk factors are those you can’t change, including

Age: less than 10 percent of people in their 20s and 40 percent of people in their 60s

warning signs of metabolic syndrome can appear in childhood.

Race. Hispanics and Asians seem to be at greater risk of metabolic syndrome.

Genetic factors : family history of metabolic syndrome ,DM,PCO

Metabolic Syndrome Risk Factors

Diseases That Increase Risk of Developing Metabolic Syndrome

History of diabetes

type 2 diabetes ( 75%of DM) gestational diabetes

Other diseases

High blood pressure, Cardiovascular disease(37%,especialy women) CHD(50%) Polycystic ovary syndrome Fatty liver

Signs

Extra weight around your waist (central or abdominal obesity)

Diagnostic criteria for metabolic syndrome

(National Cholesterol Education Program’s Adult treatment Panel II(ATPIII))

Diagnostic criteria for metabolic syndrome

World Health Organization(WHO)

Pathophysiology of the metabolic syndrome

Molecular mechanisms of insulin action and insulin resistance

Proposed mechanisms center around 3 themes:

effects of mild to moderate hyperglycemia effects of compensatory hyperinsulinemia effects of unbalanced pathways of insulin action

Dysfunctional energy storage and obesity

Dysfunctional Energy Balance

Triglycerides and fatty acids(molecules of energy storage and utilization)

Triglyceride stored physiologically in small peripheral adipocytes

Energy In > Energy Out

With obesity, excess triglyceride goes to hepatocytes (fatty liver),skeletal myocytes, visceral adipocytes,

abnormal large peripheral adipocytes

Excess triglyceride leads to insulin resistance in these cells and metabolic syndrome with increased

cardiovascular disease

Insulin resistance

Compensatory hyper insulinemia to maintain euglycemia

Obesity Dyslipidemia due to high fatty acid flux

Metabolic syndrome

insulin resistance

Increased atherosclerosis and cardiovascular disease

Pathophysiology of NAFLD

No hepatic processes

Lifestyle ( decreased physical activity and current patterns of food consumption

are Involved in the epidemics of obesity and type 2 diabetes mellitus)

Fat mass (Increased fat mass is an essential pathophysiologic factor in NASH)

Fat distribution (increased risk for NASH is associated with central obesity and

increased lipolysis of visceral tissue and an increased supply of FFAs to the liver )

Insulin resistance

Hepatic processes

Insulin resistance Insulin resistance is a state in which a given

concentration of insulin produces a less-than-expected biological effect.

Insulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain glycemic control and to prevent ketosis.

high levels of insulin in the blood as a marker of the disease rather than a cause.

It is estimated that 70 to 80 million Americans have the combination of diseases caused by insulin resistance or metabolic syndrome.

presentation of insulin resistance

• The presentation of insulin resistance depends on the type and stage of the insulin-resistant state.

• Most patients have 1 or more clinical features of the insulin resistant state.

• Many patients do not develop overt diabetes despite extreme insulin resistance.

• Other patients present with cases of severe hyperglycemia that require large quantities of insulin (>200 units)

Patients may present with the following:

Metabolic syndrome (syndrome X) patient may be asymptomatic in spite of the presence of some, or

even most, of the components of insulin resistance syndrome

Obesity (most common cause of insulin resistance) or history or excessive body weight

Type 2 diabetes mellitus (chronic or acute [during severe decompensation] )

A diagnosis of IGT

History of biochemical abnormalities: dyslipidemia, detected during routine screening or workup for a cardiovascular disease

History of hypertension

Symptoms of coronary artery disease

Symptoms related to other macrovascular disease (eg, stroke, peripheral vascular disease)

Microvascular angina

Combination of hyperglycemia and virilization

Type A, affects young women, is characterized by severe hyperinsulinemia, present with obesity and features of hyperandrogenism.

Polycystic ovary syndrome (PCOS)

Type B syndrome – presentation of hypoglycemia (sweating, tremulousness, irritability, consciousness).

Hypoglycemia results from interaction between insulinomimetic antibodies and the insulin receptor

Approach Considerations

In clinical practice, no single laboratory test is used to diagnose insulin resistance syndrome.

Diagnosis is based on clinical findings corroborated with laboratory tests.

Individual patients are screened based on the presence

of comorbid conditions.

WORK UPLab Studies :

Routine laboratory measurements in the evaluation of patients with insulin resistance syndrome include the following:

Plasma glucose level

Fasting insulin level A measure of the degree of insulin resistance

Insulin resistance May also be associated with hypoglycemia (autoimmune conditions)

Lipid profile

Electrolyte levels BUN , creatinine, and uric acid levels) hyperuricemia is common and is a component of the metabolic syndrome.

Urinanalysis Microalbuminuria is a marker of endothelial dysfunction

Homocysteine (H[e]) An elevated level is a risk factor for atherosclerosis, which predicts macrovascular disease. are regulated by insulin.

Plasminogen activator inhibitor (PAI)-1

HOMA-IR fasting glucose (mmol/L) X fasting insulin (µU/L) / 22.5). A value greater than 2 indicates insulin resistance.

Other Tests:

cardiac tests include echocardiography and stress testing

A risk-assessment calculator, based on data from the Framingham Heart Study for estimating

10-year cardiovascular risk, is available. This calculator estimates the 10-year risk for hard coronary heart disease outcomes (myocardial infarction and coronary death). The tool is designed to estimate risk in adults aged 20 years and older who do not have heart disease or diabetes.

For patients with insulin resistance without overt diabetes, the metabolic syndrome criteria for cardiovascular risk stratification are less sensitive than those of the Framingham Risk Score, which takes into account age, total cholesterol, tobacco use, HDL-C, and blood pressure, but not diabetes.

Non-alcoholic fatty liver disease and metabolic syndrome

Metabolic syndrome is highly prevalent among patients with NAFLD in multiple populations.

NAFLD can be considered as the hepatic representation of the Metabolic syndrome

The development of NAFLD is strongly associated with the metabolic syndrome as reflected by the fact that:

Approximately 90% of the patients with NAFLD have more than one feature of Mtes

And 33% have 3 or more criteria

With the addition of each of the components of the Mtes to NFALD increase risk of steatosis

NAFLD associated with

• Obesity (60-95%)

• Type2 DM (28-50%)

• Dyslipidemia(27-92%)

lipotoxicity plays a predominant role in the pathophysiology of both entities .

It leads to accumulation of triglycerides in liver as a result of imbalance among the

• Uptake• Synthesis• Export• oxidation of fatty acids

It is liked to increased oxidative stress and cell death in the liver, potentiating the development of liver fibrosis and progression to NASH.

Developing NASH increase with the severity of obesity.

There is a universal association between NASH and insulin resistance regardless of body mass index, suggesting that:

Insulin resistance is central pathogenesis of NASH

Genetic and environmental factors associated withnon-alcoholic fatty liver disease development

and progression

The development of NAFLD is strongly linked to obesity and insulin resistance.

There are obviously multiple factors determining NAFLD development and progression:

genetic environmental

Initial evidence for a genetic component to NAFLD comes from familial clustering studies the ethnic variation in NAFLD prevalence

adiponutrin found to be associated with high and low amounts of hepatic fat in Hispanics and African-Americans.

important environmental factors that determine risk in NAFLD: Nutrition physical activity

Excess food intake and lack of exercise weight gain

progression of liver fibrosis in NAFLD

Specific dietary antagonistic roles in the development and progression of NAFLD

In view of the role of oxidative stress in NAFLD pathogenesis several studies have examined antioxidant supplementation as a therapeutic intervention

additional environmental factor in NAFLD pathogenesis: Small intestinal bacterial overgrowthas probiotics could have a beneficial effect.

small human study treatment with antibiotics has been shown to result in an increase in fasting insulin levels.

obesity

inflammation

hyperlipidemia

Insulin resistance

NAFLD

ENVIROMENTALDietary factors

Food intakePhysical activityGut microflora

GeneticOxidative stressImmune related

Metabolic

Non-alcoholic fatty liver disease and CVD risk

In the last 5 years NAFLD has emerged as an independent risk factor for CVD.

Several studies have observed

increased carotid intima-media thickness

carotid plaques in patients with NAFLD, including children

a systematic review has found that carotid plaques are two to three times more likely to be observed in patients with NAFLD

intima-media thickness is strongly associated with NAFLD.

diagnosed by ultrasonography

increased risk for CVD in NAFLD is independent of conventional risk factors and components of the metabolic syndrome.

elevated liver enzymes are also associated with increased risk for CVD.

As the treatment of NAFLD involves correcting thesame metabolic factors as those involved in CVD, it isprudent that all patients with NAFLD be evaluated forearly atherosclerosis.

Likewise, patients presenting with the metabolic syndrome or a high Framingham risk score(118) should be evaluated for the presence of NAFLD.

Link between Fatty Liver and Kidney Diseases Scientists publishing in the "Journal of the American Society

of Nephrology" say the increase in CKD in the United States is linked to NALFD, especially among diabetics.

People who have a fatty liver condition have a 69 percent greater risk for CKD than people who don't have fatty liver.

Fatty liver might release substances that promote inflammation and contribute to kidney damage

liver enzyme that is strongly associated with risk of HTN seems to be regulated by the distribution of your body fat.

Obesity is a common factor in the diagnosis of both fatty liver and kidney problems

Treating fatty liver disease will ultimately prevent progression to chronic kidney disease

Treatment

• The diagnosis and treatment of metabolic syndrome is public health problem.

• The syndrome is associated with an increased morbidity and mortality mainly due to cardiovascular diseases.

• The treatment of patients with NAFLD should include the identification and treatment of the associated metabolic abnormalities to ameliorate the cardiovascular risk and to improve NAFLD.

• As the treatment of NAFLD involves correcting the same metabolic factors as those involved in CVD, it is prudent that all patients with NAFLD be evaluated for early atherosclerosis.

Treatment

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• 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 orpartially hydrogenated vegetable oil

IMPACT OF EXERCISE ON INSULIN RESISTANCE AND NASH

• Although the theoretical basis is strong, only limited data are available to support the recommendation of exercise as an important lifestyle change for patients with NASH

• Visceral adiposity did seem to be a major determinant of the correlation between fitness or exercise habits and NAFLD, perhaps because visceral fat is a major source of fatty acids delivered to the liver in obesity

• The currently available data support recommending exercise, but it would be reassuring to have well-conducted trials to corroborate findings in small and uncontrolled observational studies

DEFECTS IN MUSCLE THAT COULD IMPAIR THE RESPONSE TO EXERCISE

• A number of studies provide evidence that there may be some people who are not able to build muscle and increase aerobic exercise capacity,even with the most earnest attempts to exercise.

• Much of this investigation is now focusing on mitochondrial biogenesis and function.

• Petersen and coworkers evaluated lean, but insulin-resistant, offspring of diabetics and found impaired mitochondrial function, raising the possibility that genetic factors controlling mitochondrial oxidative phosphorylation and ATP production predispose to insulin resistance and the risk of developing diabetes.

IMPACT OF COMBINED EXERCISE ANDWEIGHT LOSS ON INSULIN RESISTANCE,NAFLD, AND NASH

• Studies have also shown that losing relatively small amounts of weight in the range of 5% to 10% confers significant benefits in terms of NAFLD and NASH

• The prospective cohort study of over 50,000 nurses that examined risk factors for insulin resistance and its complications over 6 years demonstrated that time watching television was strongly associated with an increased risk of developing diabetes and walking briskly for 1 hour daily reduced the risk of developing obesity by 24% and diabetes by 34%

• A large population intervention study in Germany found that exercise and caloric restriction led to improved liver fat content after 9 months

SPECIFIC EATING HABITS AND NASH

• Two common food components deserve special attention: high fructose corn syrup (HFCS) and industrial trans-fats.

HFCS

• Soft drinksare typically sweetened with a solution of 55% fructose, 41% glucose, and 4% residual complex carbohydrates.

• HFCS has desirable properties for its sweetness, its ease of handling in bulk, and its cost competitiveness compared with other sweeteners.Its regular consumption in large amounts has been associated with the development of insulin resistance and NAFLD

HFCS• At around 40 g of carbohydrate per 12-oz serving, a typical

can of cola contains the amount of sugar in about 10 sugar cubes.

• Such comparisons can be useful in discussing dietary habits with patients and especially parents of pediatric patients.

• High-dose fructose challenges the liver metabolically by depleting hepatic energy reserves because of the rapid first pass uptake of fructose by the liver and phosphorylation by phosphofructokinase.

• Fructose also impairs normal satiety mechanisms, a response that could be particularly problematic when soft drinks are consumed with excessively portioned meals.

Trans-fats

• Industrial trans-fats (ITF) found in partially hydrogenated vegetable oils (vegetable shortening) comprise a relatively new addition to the Western diet

• Only a few studies have examined the potential role of dietary ITF as a cause of liver injury, and these suggest that ITF could be a significant but overlooked contributor to the current epidemic of NASH.

• One study reported a rise in mean ALT from 22 U/L to 97 U/L in just 2 weeks in healthy medical students who ate at least two meals of fast food daily

Trans-fats

• Drug Administration labeling standards allow foods with less than 0.5 g trans-fats per serving to be labeled as ‘‘zero trans-fats,’’ editorialists have pointed out that by consuming four to five small, industry-defined, ‘‘serving sizes’’ of zero trans-fat food, ITF consumption can easily exceed the recommended daily limit of 2 g.

• Restaurant food also continues to be a major source of trans-fats, especially at a number of large national chain restaurants

PRACTICAL STRATEGIES FOR ACHIEVING LIFESTYLE MODIFICATIONSIN PATIENTS WITH NASH

• When discussing physical activity with patients, the discussion should focus on impediments to increasing physical activity and finding ways for patients to incorporate exercise into their lives on a regular basis indefinitely.

• It is often helpful to separate the benefits of exercise from weight loss. Because exercise has its own benefits in terms of a sense of well-being and improved insulin responsiveness, being discouraged about lack of weight loss should not be a reason to quit.

• To most, the idea of dieting to achieve weight loss has many negative connotations because of prior failures and typically invokes the strongly counterproductive psychology of denial. Instead of discussing diets and dieting, the focus needs to be on healthy eating habits, or the positive side of changes in eating habits

HCC, diet and metabolic factors

• A diet rich that is in polyunsaturated fatty acids and, possibly, B-carotene could reduce the risk of HCC, and high dietary GL is associated with an increased risk independently of cirrhosis or diabetes.

Diet only interventions• Six using low-to-moderate fat/moderate-to-high

carbohydrate energy restricted diets, one of which also specifically restricted iron intake

• Three groups were given low carbohydrate ketogenic diets • Two high protein diets • Two studies employed biopsy ,but only one at follow-up • The other used ALT and AST at follow-up• Three used 1H-MRS ,two used CT ,three• studies relied on ALT and AST .Only two studies had a• Control group ,in one the control group were those withlow adherence to the protocol

Diet only interventions• Interventions lasted 1–6 months and achieved mean bodyweight reductions of 4–14%.

All studies using biopsy or imaging techniques to estimate IHTAG reported reductions.

• The three studies using 1H-MRS reported absolute reductions of 4–10%and relative reductions of 42–81%. • The only study to do a post intervention biopsy (n = 5) reported reduced

inflammation andtrend towards reduced fibrosis (p = 0.07), as well as the reductionin steatosis, following a ketogenic diet and a mean weight reductionof 14% • Five out of seven studies reporting liver enzymes showed reductions and one

showed no change. • The study that found an increase in ALT and AST, but only in women, suggested• this might have been due to the analysis being done before• weight had stabilised .• Five out of six studies reporting glucose control/insulin sensitivity noted

improvements.

Exercise only interventions• Two studies published contained exercise only groups • The interventions involved moderate intensity aerobic activity.

Four weeks of stationary cycling three times per week resulted in a reduction in 1H-MRS measured IHTAG of 1.8%, relative reduction of 21%, but no statistically significant change in HOMA relative to either baseline or control .

• Three months of aerobic exercise including brisk walking/jogging or rhythmic aerobic exercise resulted in a 47% and 48% reduction in ALT and AST,

• Exercise only intervention groups in both studies maintained their baseline weight suggesting that weight reduction is not a prerequisite for liver fat or biomarker reduction.

Exercise combined with diet

• Seven studies employed a selection of behaviour change methods to decrease energy intake and increase physical activity/exercise over 3–12 months ,these studies provided general physical activity guidelines, but did not prescribe specific exercise protocols.

The focus was predominantly on body weight reduction and

Discussion• Weight reductions of 4–14% resulted in statistically significant

relative reductions in IHTAG of 35–81%. The magnitude of change strongly correlated to degree of weight reduction,

• There is also limited evidence that physical activity/exercise can lead to modest reductions in IHTAG without weight change.

• Low (800–1800 kCal/day) and very low-calorie diets• (<800 kCal/day), and/or carbohydrate restriction (20–50 g/d)

resulted in the most rapid reductions in body weight and IHTAG.• The combination of caloric and carbohydrate restriction resulted in

a 30% reduction in IHTAG and equally substantial improvements in glucose control and insulin sensitivity within 48 h; a time when weight reduction can only be small and largely accounted for by glycogen depletion and water loss

1) The first line is Lifestyle modificationWeight reduction (dietary change)

Increased physical exercise

Behavioral modification is the

most important

Self monitoring of eating and exercise

Stimulos control techniques

Problem solving

2) Pharmacological treatment

Orlistat

Phentermine

Sibutramine

(FDA) Pharmacotherapy in the treatment remains uncertain

3) Surgery

Weight reduction

1) Should optimally achieve a 5-10% weight reduction at which steps of the disease

In the long term

Changing dietary composition

TG deposition in the liver

Excessive influx of FFA from endogenous flat depots

Increased de novo hepatic lipogenesis

Post prandial

Fat

Subtypes of fat (saturated, unsaturated) may be important than their total amount.

Saturated fat intake plasma Glutathione (oxidized glutathione): oxidative stress

Two types of fat are important:

1) Trans Fatty Acid (TFA):

Risk of developing insulin resistance

LDL

HDLTG

Risk of coronary heart disease

NAFLD

2) Mono unsaturated Fatty Acid (MUFA):

n-9 oleic acid

Olive oilNuts

Avocado

De novo lipogenesis ( hepatic ch REBP)

Improved insulin resistance

VLDL and fasting plasma triacylglycerol

The flux of FFA s from peripheral adipose tissue back to liver

Release of TG from liver

HDL without adverse effect on LDL

3) Poly unsaturated Fatty Acids (PUFA): omega-3 LFT

Cholestrol

Induce de novo fatty acid synthesis in hepatocytes

Added sugar and soft drink

Sucrose_rich diet hepatic synthesis of TG

NAFLD patients should limit their fructose consumption

Beverages

Cola. Soft drinks: caramel coloring (glycation end products)

>500 soft drink intake = NAFLD

Routinely questions regarding soft drink consumption as part of patient history

Western dietary pattern and fast food

Consumption of fructose, soft drinks, meat, saturated fat

Consumption of fiber, PUFA, fish or omega-3 and vitamins

In one study > twice a week = 4.5 kg extra body weight = two fold greater insulin resistance

In other study: 18 healthy young students with at last 2 fast food meals aday for 4 weeks

11 had elevated ALT at one week

In clinical evaluations of subjects with ALT

Questions about Alcohol and soft drink

Recent excessive intake of fast food

Caffeine

Two coffee cup/day =less severe hepatic fibrosis 100mg of caffeine in a cup

Totally: high energy density and portion size

high fat and saturated fat high refined carbohydrate

low fiber

high Fructose corn syrup

caramel coloring

red meat

industrially produced trans fatty acids

Physical activity:

Over flow the FFA to liver

and local inflammation

upregulation insulin reseptor in muscle

Whole body lipid oxidation

Low long –term : walking , swimming or cycling

Even small increment in regular P.A

3 cycle sessions per week (30-45 min) for 4 weeks

21% hepatic TG

12% visceral adipose14% plasma FFA

Aerobic exercise: more extensive effects

Hepatic insulin sensitivity

Glucose production

Abdominal fat

Resistance exerciseWithout weight loss

+

Unchanged hepatic fat

CDC & AHA > 30 min of moderate intensity all days

Vigorous intensity 3 times in a week 20 min

OR

>>

Potentially therapeutic dietary supplement

Be carefull : increase risk of hemorrhagic stroke

2)Vit D: serum 25(OH)D associated with insulin sensitivity & B cell function

1) Vit E : 300-1000 IU/d

A combination of educational , behavioral and motivational strategies is required to help

patients achieve life style change.

Multidisciplinary teams including : dietitiansPsychologistsPhysical activity supervisors`

Therapeutic Strategies

• Few effective liver-specific therapies are available.

• Thus, current treatments are primarily directed towards cardiovascular risk reduction and improving the metabolic variables which contribute to disease progression

• To achieve optimal control of obesity,diabetes, hypertensionand dyslipidaemia,

• multidisciplinary approach is ideal, in which HepatologistDietitian Diabetologist Diabetic specialist nurse can see patients.

•It is unlikely that one single treatment will represent a panacea for NAFLD; rather the combination of• several modalities of treatment, such as weight loss Diet Exercise Surgery pharmacological therapy.

INDICATIONS FOR TREATMENT

• Indications for Pharmacotherapy not been established.

• The spectrum of NAFLD covers bland steatosis and steatohepatitis.

• Currently it is believed that only steatohepatitis carries a significant risk of liver disease progression, while the risk associated with bland steatosis is largely extrahepatic.

• Therefore first-line diet and lifestyle changes should be enforced in any patient with NAFLD

• Pharmacologic therapy specifically aimed at improving the liver condition is most certainly necessary only in patients with steatohepatitis

PHARMACOLOGIC TREATMENTS

• The need for treatment in NAFLD is based on the concern for progressive liver disease

and cirrhosis. • Natural history studies indicate this occurs in

a minority of patients, • the high prevalence of the disease means an

effective treatment could have major economic and health benefits.

Insulin sensitizers

• • Glitazones• • Weight loss agents• • Metformin• • CB1R blockers

Thiazolidinediones

• (TZDs) function as selective agonists for peroxisome proliferator activated nuclear receptor.

• Decreasing hepatic fatty acid levels (by decreasing lipolysis and increasing -oxidation)

• Redistributing fat content from the liver to peripheral adipose tissue.

• Promoting insulin sensitivity by facilitating preadipocyte differentiation into insulin-sensitive adipocytes.

Summary of trials involving Pioglitazone therapy for NAFLD

• Abbreviations: RCT, randomized controlled trial; , improvement; , no effect.

Summary of trials involving Rosiglitazone therapy for NAFLD

• Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.

• Discontinuation of TZDs results in a return to pretreatment NASH histology and serum markers, suggesting that TZD therapy would have to be maintained indefinitely

for continued treatment response.22

• TZD therapy, especially with pioglitazone, seems to be an effective treatment for NASH

• but needs to be given indefinitely and, given its propensity for weight gain, it needs further study.

• It can be considered one of the preferred agents in diabetic patients with NASH

Weight loss agents

• Orlistat is a pancreatic and gastric lipase inhibitor which inhibits the absorption of up to 30% of dietary triglycerides .

• Side effects such as diarrhoea and bloating • loss of ≥5% BW correlated with improvements in

insulin sensitivity and steatosis, whereas a loss of ≥9% BW was required for an improvement in overall NAS

• Larger studies with longer treatment durations are required

• Sibutramine is a serotonin and noradrenaline reuptake inhibitor

• Rimonabant, a cannabinoid receptor antagonist

• Were taken off the market.

• Glucagon-Like Peptide-1 (GLP-1) analogues• Exenatide and Liraglutide• Weight loss of 4.8 and 7.2 kg in those taking 1.8 and

3.0 mg liraglutide for (20-week trial)• Liraglutide also reduced blood pressure and the

prevalence of prediabetes• Genetic and pharmacological elevated levels of GLP-1

in rodent models have been shown to reduce insulin resistance, liver enzymes and hepatic steatosis [88,89]. Although human clinical trials examining the specific role of GLP-1 analogues in NAFLD patients are yet to be published,

Metformin

• Metformin, a biguanide, is traditionally considered first-line treatment for non–insulin dependent diabetes.

• Because there is a high prevalence of diabetes in patients with NAFLD, targeting insulin resistance with metformin seems like an appropriate pharmacologic option

Summary of trials involving Metformin therapy for NAFLD

Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.

• Recent trials continue to provide mixed results.• Omer and colleagues21• compared metformin with rosiglitazone in a 1-year

randomized trial of diabetic NASH patients.• Metformin significantly reduced the waist

circumference and BMI of patients, but no effect on transaminase levels or NAS. On the other hand, the combination of

• metformin with rosiglitazone significantly improved transaminase levels and NAS,

• suggesting that metformin may have a role in potentiating TZD effects in NAFLD.

• Metformin may improve insulin sensitivity in NAFLD, but its effects on transaminases,

steatosis, inflammation, and fibrosis remain unclear.

Further trials of longer duration and larger sample sizes that look at histologic outcomes are necessary before metformin can be recommended for use in NAFLD

Vitamin E

• Vitamin E (-tocopherol) is a naturally occurring antioxidant. Its effects in NASH may be secondary to its function as a

• free radical scavenger or its ability to• inhibit cytokines such as transforming

growth factor (TGF-), which plays a role in hepatic stellate cell activity and fibrogenesis as shown in rat models

Summary of trials involving Vitamin E therapy for NAFLD

• Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect.

effect

• Vitamin E treatment seems to be beneficial in NASH, but there is a note of caution.

• High-dose vitamin E therapy has been associated with increased mortality in other studies,31 and most NAFLD trials have used doses of vitamin E above the current

recommended dose..• It would be prudent until more data emerges to use

vitamin E selectively in NASH patients with more severe changes on histology.

• Combination regimens including vitamin E cannot currently be recommended.

Probucol

• Probucol is a lipid-lowering agent with potent antioxidant properties, allowing it to

function as a free radical scavenger

• Merat and colleagues40 have conducted 3 trials of probucol in NAFLD.

• In their original pilot study, • 500 mg of probucol for 6 months • significantly reduced transaminase• as well as reduced total cholesterol.• However, most of the reduction in cholesterol

was due to a drop in high-density lipoprotein cholesterol (HDL);

• LDL and TG levels did not change significantly

• Probucol can lower HDL levels and cardiac arrhythmias have also been seen.

• Therefore, until randomized,controlled trials show consistent histologic benefits and no adverse effects,

• probucol cannot be recommended for use in NAFLD.

Pentoxifylline

• Pentoxifylline is a phosphodiesterase inhibitor,

• resulting in decreased activity of TNF,TGF. Therefore,

• pentoxifylline could theoretically function as an antioxidant, antifibrotic,and insulin-sensitizing agent in NAFLD

Summary of trials involving Pentoxifylline therapy for NAFLD

• Abbreviations: n/a, not available; RCT, randomized controlled trial; , improvement; , no effect

• Pentoxifylline at 1200 mg/d is a safe and promising potential agent in NAFLD.

• However, until a larger placebo-controlled study evaluates histologic end points,

pentoxifylline cannot be recommended.

UDCA

• UDCA is a secondary bile acid that plays a role in lipid metabolism by

• regulating intestinal cholesterol uptake.• preventing the formation of cholesterol

gallstones, • UDCA has also been hypothesized to have

anti-apoptotic and anti-oxidant effects.50,51

Summary of trials involving UDCA therapy for NAFLD

• Abbreviations: n/a, not available;

• UDCA has not consistently shown any superiority over placebo in multiple large trials until convincing histologic evidence is presented

UDCA cannot be recommended as a first-line agent for NAFLD.

Endoscopic Treatment

• In comparison with surgery, such as laparoscopic sleeve gastrectomy,

• Intragastric balloon placement is equally effective in inducing weight loss and

• has less morbidity,• but lacks the ability to maintain weight loss

when the balloon is removed• Spanish study in 714 consecutive patients

demonstrating a decrease in mean BMI of 6.5 kg/m2 (from 37.6 to 31.1 kg/m2).

SURGICAL OPTIONSBariatric Surgery

• In 1991 that the National Institutes of Health issued a consensus statement that

• bariatric surgery was an appropriate indication for patients with a BMI over 40 kg/m2

• or 35 kg/m2 with comorbidities

• laparoscopic bariatric surgery such that it is• among the most common operative

procedures performed in the United States with more than 200,000 procedures in 2009.6

• The most popular is the Roux-en-Y gastric bypass RYGB, which typically

• leads to the greatest and most durable decrease in BMI.

Summary of Bariatric surgery trials for NAFLD

• Abbreviations: n/a, not available; , improvement; , no effect

• A recent review and meta-analysis of 15 studies of bariatric surgery in

• NAFLD with paired liver biopsy data determined that the

• vast majority of patients had improvement in steatosis and NASH, with

• resolution seen in 70% and • fibrosis regression in 66%.

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

• According to the United Network of Organ Sharing, the first adult OLT for

• a definitive diagnosis of NASH cirrhosis took place in 1996 and was only a tiny fraction of the total adult OLT performed in that year (0.11%).

• Since then, the number of OLTs• performed for NASH cirrhosis has increased by

more than 40-fold in 10 years

QUASTIONS :

• Who should be treated with drug agents?• What is the best method for the treatment of each patient? and When we can stop the treatment?