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Hepatosteatosis. Prof Samir Helmy Assaad-Khalil Unit of Diabetes & Metabolism Alexandria Faculty of Medicine. 2007. Agenda. Definition Common Causes of Steatosis Prevalence Data Ethnic and gender differences Relationship between fatty liver disease & Met. Syndrome

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hepatosteatosis
Hepatosteatosis

Prof Samir Helmy Assaad-Khalil

Unit of Diabetes & Metabolism

Alexandria Faculty of Medicine

2007

agenda
Agenda
  • Definition
  • Common Causes of Steatosis
  • Prevalence Data
  • Ethnic and gender differences
  • Relationship between fatty liver disease & Met. Syndrome
  • Pathogenesis of fat accumulation in the liver
  • Screening tests / Diagnosis
  • Management
definition
Definition
  • Hepatosteatosis is defined as fat deposition in the liver that exceeds 5% of the total weight of liver, or with > 5% of hepatocytes containing fat deposits under light microscopic examination
  • It occurs under several disease states.
slide4

Fatty disorders of the liver may be

    • Alcoholic (AFLD)
    • Non-alcoholic.(NAFLD)
    • NAFLD includes both:
        • Hepatic Steatosis
        • NASH

l

l

l

l

causes of nonalcoholic fatty liver disease
Causes of Nonalcoholic Fatty Liver Disease

*HIV, human immunodeficiency virus.

inborn errors of metabolism associated with steatosis
Inborn Errors of Metabolism Associated With Steatosis
  • Abetalipoproteinemia
  • Familial hepatosteatosis
  • Galactosemia
  • Glycogen storage disease
  • Hereditary fructose intolerance
  • Homocystinuria
  • Systemic carnitine deficiency
  • Tyrosinemia
  • Resfum\'s disease
  • Schwachman\'s syndrome
  • Weber-Christian syndrome
  • Wilson\'s disease
acquired metabolic disorders associated with steatosis
Acquired Metabolic Disorders Associated With Steatosis
  • Diabetes mellitus
  • Obesity
  • Inflammatory bowel disease
  • Jejuno-ileal bypass
  • Kwashiorkor and marasmus
  • Serum lipid abnormalities
  • Starvation and cachexia
  • Severe anemia
  • Total parenteral nutrition
drugs toxins associated with steatosis
Drugs/Toxins Associated With Steatosis
  • Antibiotics
    • Azaserine
    • Bleomycin
    • Puromycin
    • Tetracycline
  • Other drugs
    • Amiodarone
    • Coumadin
    • Dichloroethylene
    • Ethionine
    • Ethyl bromide
    • Estrogens
    • Flectol H
    • Glucocorticoids
    • Hydrazine
    • Hypoglycin
    • Orotate
    • Perhexilenemaleate
    • Safrole
  • Metals
    • Antimony
    • Barium salts
    • Borates
    • Carbon disulfide
    • Chromates
    • Phosphorus
    • Rare earths of low atomic numbers
    • Thallium compounds
    • Uranium compounds
  • Cytotoxic/cytostatic drugs
    • l-Asparaginase
    • Azacytidine
    • Azauridine
    • Methotrexate
prevalence data risk factors
Prevalence Data: Risk Factors

T2 DM

28-55%

Obesity

60-95%

Hyperlipidemia

20-92%

distribution of nafld by racial ethnic group

Caucasian African-American Latino – Hispanic Asian Other

Distribution of NAFLD by Racial/Ethnic Group

Estimated Alameda County

Population (represented by KP Membership)

NAFLD Study Population

disease associations in different racial ethnic groups with nafld
Disease Associations in Different Racial/ Ethnic Groups With NAFLD

* Asian versus other groups combined

* Asian versus other groups combined

clinical features of ms in patients with nash
Clinical features of MS in patients with NASH

Yasemin H. et al., Annals of Hepatology 2006; 5(2): April-June: 109-114

chronic hyperinsulinemia carbohydrate ingestion
Chronic hyperinsulinemia & carbohydrate ingestion
  • Chronic hyperinsulinemia & carbohydrate ingestion stimulate de novo lipogenesis by stimulating the activity of lipogenic enzymes such as the sterol regulatory element binding proteins (SREBP-1c).
  • The FFA stored in the liver can originate from hydrolysis of dietary chylomicrons or adiposity.
srebps suppress irs 2 mediated insulin signalling in the liver
SREBPs suppress IRS-2-mediated insulin signalling in the liver
  • Insulin receptor substrate 2 (IRS-2) is the main mediator of insulin signaling in the liver, controlling insulin sensitivity.
  • Sterol regulatory element binding proteins (SREBPs) directly repress transcription of IRS-2 and inhibit hepatic insulin signaling.

Ide T et al., Nat Cell Biol. 2004 Apr;6(4):351-7.

slide16

Pathogenesis

“2 Hit” Paradigm

  • “Second hit” – Intrahepatic oxidative stress
  • Lipid peroxidation
  • TNF-alpha, cytokine cascade

“First hit” – Excess fat accumulation

oxidative stress mitochondrial changes
Oxidative Stress & Mitochondrial Changes
  • Chronic oxidative stress has been implicated with

a) Formation of lipid hydroperoxides.

b) Induction of certain microsomal enzymes e.g. cytochrome P450 2 El.

  • Mitochondrial changes:

a) Mitochondrial damage with inhibition of mitochondrial electron transport chain activity.

b) Release of mitochondrial free radicals.

c) Depletion of mitochondrial glutathione pools.

kupffer s cell dysfunction
Kupffer`s Cell Dysfunction
  • Hepatic steatosis also promotes:

a) Kupffer’s cell dysfunction

b) Impaired phagocytosis

c) Chronic low grade endotoxemia.

  • Endotoxemia stimulate hepatic production of:

a) TNF- 

b) IL-6 and IL-8

c) Promote neutrophil chemotaxis & an inflammatory

response.

adiponectin
Adiponectin
  • Decreased serum adiponectin concentrations correlates with hepatic fat content in patients with type 2 diabetes.
  • Hepatocyte growth factor (HGF) is not only an antiapoptotic and antifibrotic factor of liver, but it is also an adipokine.
slide20
Serum leptin & NASH studies in humans Leptin in the Field of Hepatic Fibrosis:A Pivotal or an Incidental Player?

CVH, chronic viral hepatitis; NASH, nonalcoholic steatohepatitis;

NAFLD,nonalcoholic fatty liver disease

Sotirios K. et alDig DisSci DOI 10.1007/s10620-006-9126-0

serum leptin levels are associated with tamoxifen induced hepatic steatosis
Serum Leptin Levels Are Associated With Tamoxifen-Induced Hepatic Steatosis

Serum leptin levels in patients with a normal liver or stable hepatic

steatosis (group 1) and with increased hepatic steatosis (group 2)

NazanGünel et al., Curr Med Res Opin 19(1):47-50, 2003.

ghrelin in nafld
Ghrelin in NAFLD
  • Ghrelin is reduced in NAFLD vs. controls
  • Insulin resistance is a major factor controlling ghrelin levels in subjects with and without NAFLD.
tumor necrosis factor tnf gene
Tumor necrosis factor-α (TNF-α) gene
  • Tumor necrosis factor-α (TNF-α) gene expression is increased in adipose tissue in insulin resistant obese and type 2 diabetic patients.
  • In patients with NASH, TNF-α gene expression is increased in both hepatocytes and adipose tissue.
the microbial theory
The microbial theory
  • Conversion of choline into methylamines by microbiata in strain 129S6 on a high-fat diet reduces the bioavailability of choline and mimics the effect of choline-deficient diets, causing NAFLD.
  • Fatty liver due to chronic choline-deficient diet exacerbates liver hepatitis, which is predominantly facilitated by T cells.
  • Delayed intestinal transit may contribute to intestinal bacterial overgrowth (IBO).

Soza A et al., Dig Dis Sci. 2005 Jun;50(6):1136-40.

rosiglitazone
Rosiglitazone
  • Rosiglitazone decreases liver fat and increases insulin clearance. The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations.
  • Despite this beneficial effect of TZDs, in certain individuals however, in addition to increasing fat mass, TZDs have the potential to exacerbate underlying hepatosteatosis.
hepatic iron
Hepatic iron
  • Many patients with NASH have biochemical evidence of iron overload.
  • Yet, it has been suggested that the iron overload may be a result of hemachromatosis gene mutation which is ethnic specific and is probably not seen outside the population of Anglo-Celtic Caucasian descent.

Uraz S et al., Dig Dis Sci. 2005 May;50(5):964-9.

inflammatory liver steatosis caused by il 12 and il 18
Inflammatory liver steatosis caused by IL-12 and IL-18
  • Acute fatty degeneration in the liver is caused by various agents, such as aspirin, valproic acid, and ibuprofen, that directly inhibit mitochondrial beta-oxidation of fatty acid and oxidative phosphorylation.
  • IL-12 and IL-18 may mediate inflammatory hepatosteatosis through impairment of the microcirculation, which leads to mitochondrial dysfunction in hepatocytes.

Kaneda M et al., J Interferon Cytokine Res. 2003 Mar;23(3):155-62.

the serum levels of il 1 b il 6 il 8 and tnf a in nonalcoholic fatty liver
The Serum Levels of IL-1b, IL-6, IL-8 and TNF-a in Nonalcoholic Fatty Liver

Serum cytokine values of NAFL and control groups.

  • IL-8 might play a more important role in the pathogenesis of liver steatosis than TNF-a, IL-1b and IL-6.

Ülyas Tuncer et al., Turk J Med Sci 33 (2003) 381-386

post transplant nash
Post-transplant NASH

Re-transplantation

Cirrhosis

12.5%

NASH

33%

Steatosis

60%

slide30
Steatosis in chronic hepatitis B : a result of metabolic causes attributable to the host rather than the effect of the viruses.

Comparison of BMI of groups with & without

steatosis(P<0.05

Comparison of cholesterol and triglyceride levels

of groups with & without steatosis (P<0.05).

Altlparmak E et al. Causes of steatosisWorld J Gastroenterol May 28, 2005 Volume 11 Number 20

nash in patients with hcv
NASH in patients with HCV
  • The presence of NASH in patients with HCV is strongly associated with:
      • Features of the metabolic syndrome
      • Is a risk factor for advanced fibrosis with bridging.
  • Risk factors for advanced fibrosis in patients with NASH & HCV are:
      • Weight.
      • Presence of diabetes.
      • Presence and degree of cytological ballooning.
slide32

Pathogenesis of NASH

The liver metabolizes FFAs (partly mediated by lipase which is inhibited by insulin)

Interruption of insulin signaling in hepatocytes causes fatty liver. Increase hepatic FA content causes hepatic IR

Insulin resistance (IR)

FFA

When FFAs accumulate in the liver , they are oxidized by mitochondria .

When FFAs accumulation exceeds oxidation ,the triglycerides and fat accumulate in the liver

- Insulin signaling

-  fat in liver

- TNF

TNF  plays an important role in IR evidenced by improvement of insulin sensitivity by genetic disruption of type 1 TNF receptors

Bacterial endotoxins

Steatosis

Endotoxins from intestinal bacteria escape into the mesenteric blood & trigger a sustained hepatic inflammatory cytokine response (TNF).

Lipid peroxidation

TNF

Cytokines

NASH patients have higher concentration of total & FFA and total saturated & monounsaturated FAs, mainly due to the increase of: Hexadecanoic acid, Hexadecenoic acid &

Octadecenoic acid. While absolute PUFA was not increased

Chronic oxidative stress with a) Induction

of certain microsomal enzymes

(cytochrom P450 2 El) b) Lipid

peroxidation. c) Mitochondrial damage

with depletion of mitochondrial glutathion

pools and release of mitochondrial free

radicals which induce lipid peroxidation

of hepatocyte membranes; initiate an

inflammatory response with release of

cytokines (TNF , IL-6, IL- 8) and

stimulate fibrosis.

Steatohepatitis

Reduced antipyrine clearance (Cl-AP (reflects hepatic microsomal oxidative capacity)

Iron

TGF-

Cytokines

Hepatic iron may contribute to the pathogenesis

of NASH by : 1- Induction of lipid peroxidation of

organelle membranes resulting in membrane disruption.

2- Impaired mitochondrial oxidative metabolism. 3-

Hepatocyte injury and death. 4- Lipocyte activation and

stimulation of collagen type I gene activation & fibrosis.

Cirrhosis

clinical features of nash
Clinical Features of NASH
  • Symptoms
    • Vague (fatigue, malaise, right upper quadrant discomfort)
    • Variable
    • Mostly absent
  • Signs
    • Hepatomegaly common
    • Splenomegaly in some
    • Portal HTN unusual
  • Laboratory values
    • Increased AST, ALT typical
    • +/2 increased alk. phos., GGT
    • Increased cholesterol, triglycerides common
    • Increased glucose common
    • Viral markers (2)
    • Autoantibodies (2)
    • Iron studies abnormal sometimes
  • Imaging
    • Fatty liver
transaminases
Transaminases
  • Alanine transaminase (ALT) levels are higher than aspartate transaminase (AST) levels in most instances.
  • AST level may occasionally be higher than the ALT level, especially in the presence of cirrhosis.
  • The usual AST/ALT ratio is < 1 in patients with NASH and may be used to differentiate it from alcoholic liver disease (> 2 in the latter).
  • NASH can present with normal ALT values (in 20-25% of patients) despite the presence of a full histologic spectrum.
symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease
Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liverdisease
  • Approximately one-half of NAFLD patients, whether NAFL or NASH, have Syndrome of Sleep Apnea.

Singh H et al., Dig Dis Sci. 2005 Dec;50(12):2338-43.

demonstration of fat in the liver staging grading
Demonstration of fat in the liver, staging & grading
  • The presence of fat in the liver can be demonstrated by various imaging modalities; however, no current noninvasive method can distinguish NASH from NAFLD.
  • Liver biopsy remains the gold standard for staging and grading
histologic criteria
Histologic criteria
  • There are 2 histologic patterns of NASH:
  • Steatosis.
  • Steatohepatitis
  • The principle histologic features of NASH are:
  • The presence of macrovesicular fatty change in hepatocytes
  • Displacement of the nucleus to the edge of the cell.
  • Leucocytic infiltration in steatohepatitis.
imaging
Imaging
  • Transabdominal ultrasound is a sensitive, noninvasive method for detecting NAFLD. However, diagnostic criteria are highly operator-dependant and non-standardized
  • Spleen-minus-liver attenuation difference (DeltaS-LA) derived from CT shows a good correlation with the pathology of hepatosteatosis.

Duman DG et al.,Dig Dis Sci. 2006 Feb;51(2):346-51.

scintigraphy
Scintigraphy
  • Using scintigraphy, a strong, significant inverse correlation between the severity of steatosis, hepatic triglycerides content, and 99mTc-mebrofenin uptake rate was observed.
  • In the future, noninvasive "dynamic" breath tests may disclose specific alterations in metabolic pathways.
proposed histologic spectrum nafld
Proposed Histologic Spectrum NAFLD

Fat

Ballooning

Degeneration

Fibrosis

+/-Mallory Bodies

Fat

Inflammation

Ballooning

Degeneration

Fat

+

Inflammation

Stage IV

Stage III

Stage II

Stage I

FAT

Matteoni et al, Gastroenterol 1999

Examples of non-alcoholic fatty liver disease (NAFLD)

nash as a cause of end stage liver disease
NASH as a Cause of End-Stage Liver Disease
  • Primary indication for OLT in 31/1,207 (2.6%) of patients evaluated at Mayo between 1993-98.
  • 16/546 (2.9%) underwent transplantation for end-stage NASH

OLT= Organ Liver Transplant

Charlton et al. Liver Transpl, 2001

nash and effect of weight loss
NASH and effect of weight loss
  • Histological & laboratory improvement occurs with a 10% decrease in body weight.
  • However, in some patients, rapid weight loss may result in mild increase in inflammatory lesions (hepatitis), despite the regression of steatosis.
  • This may result from rapid mobilization of fatty acids or cytokines from adipose tissue, especially visceral fat.
silymarin
Silymarin
  • Therapeutic approaches include silymarin, the seed extract of milk thistle, which is a mixture of flavonolignans
  • A hepatoprotective agent stimulating secretion of adiponectin.
  • This flavanoid has also antioxidant, antifibrotic, and membrane-stabilizing effects.

Schuppan D et al., Hepatology 1999;30:1099-1104

vitamin e betaine
Vitamin E & Betaine
  • Vitamin E, an antioxidant agent, reduces liver inflammation and necrosis.
  • Betaine, a naturally occurring choline metabolite, improves both biochemical parameters and liver histology.
metformin
Metformin
  • Metformin improves biochemical indices of hepatocellular injury and insulin resistance
    • Long-term metformin (500 mg 3 times /day for 4 months) resulted in:
      • Reduced transaminase levels, which returned to normal in 50% of actively-treated patients.
      • Improved insulin sensitivity
      • Decreased liver volume by 20%.
    • Mechanism of action of metformin in NASH:
      • Inhibits the hepatic TNF- activity .
      • Inhibits the expression of UCP-2 .
ppar agonists
PPAR Agonists
  • Thiazolidinediones reduce hepatic fat stores in type 2 diabetes mellitus.
  • PPAR-alpha agonists exert antioxidative effects by inducing antioxidant enzymes, in addition to diminishing steatosis
insulin therapy
Insulin therapy
  • Insulin therapy improves hepatic insulin sensitivity
  • It slightly but significantly reduces liver fat content, independent of serum adiponectin.
patients receiving long term total parenteral nutrition
Patients receiving long-term total parenteral nutrition
  • Patients receiving long-term total parenteral nutrition may develop NAFL partially because of choline deficiency.
  • Besides, bacterial overgrowth is enhanced in the resting intestines.
  • Choline supplementation has been reported to improve or revert hepatic steatosis.

Buchman AL et al., Gastroenterology 1992; 102:1363-1370

Buchman AL,et al. Hepatology 1995;22:1390-1403

Pappo I et al., J Clin Res 1991;51:106-112

Freud HR rt al., J Surg Res 1985;38: 356-363

iron depletion
Iron depletion
  • Hepatic iron overload is frequent in NAFLD, and iron depletion improves liver function tests and insulin resistance.
  • The addition of iron depletion therapy to standard diet/exercise reduces serum ALT levels in NASH independently from iron stores, thus representing a promising effective, safe, and low-cost therapy.
glucagon like peptide 1
Glucagon-like peptide-1
  • Glucagon-like peptide-1 (GLP-1), reverses hepatic steatosis.
fat reduced diet
Fat-reduced diet
  • Protecting hepatocytes ATP stores & inhibiting Cyp2E1 activity by dietary modifications (fat-reduced diet), may be beneficial in NAFLD patients.

Chavin K et al., J Biol Chem 1999;274:5692-5700

Cortez-Pinto H et al., JAMA 1999;282:1659-1664

Weltman MDet al. Hepatology 1998;27:128-133

slide53
Surgical treatment (gastroplasty) improves metabolic abnormalities & hepatic lesions of NAFLD in long-term observations

Significant improvement of histologic lesions 8 months after gastroplasty. H&E ×250.

Diffuse grade 3 steatosis & steatohepatitis in liver biopsy taken during gastroplasty.

H&E ×250.

K. JASKIEWICZ et al. , Digestive Diseases and Sciences, Vol. 51, No. 1 (2006), pp. 21–26

take home message
Take Home Message
  • The main risk factors for steatosis are obesity, type 2 diabetes & dyslipidemia
  • Ethnic & gender differences have important implications for the development of steatosis-related liver disease.
  • Met. syndrome & adiponectin concentrations are independently associated with the probability of steatosis
  • Intestinal bacterial overgrowth has been suggested to play a pathogenic role in patients with nonalcoholic fatty liver disease (NAFLD).
  • Hepatic iron may contribute to the pathogenesis of NASH
slide55

Take Home Message

  • IL-12 and IL-18 may mediate inflammatory hepatosteatosis
  • Approximately one-half of NAFLD patients, have SOSA.
  • The most common abnormality in liver function tests is a two- to fivefold elevation in ALT and AST
  • Liver biopsy remains the gold standard for staging and grading
  • Transabdominal ultrasound is a sensitive, noninvasive method for detecting NAFLD. However, diagnostic criteria are highly operator-dependant and non standardized
slide56

Take Home Message

  • Current management includes weight loss, treatment of diabetes and lipid disorders as well as avoidance of alcohol and hepatotoxic drugs.
  • Weight loss (about 10%) improves biochemical & histological profiles in the majority of obese NASH patients
  • Potential future therapies include constraining macrophage activation using antioxidants, the use of antibiotics, anti-cytokines & PPAR agonists. Lastly minimizing Cyp2E1 activity by dietary modification.
  • Iron depletion therapy reduces serum ALT levels in NASH & may be a promising low cost, future therapy.
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