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Update on fatty liver diseaseRob Goldin

Centre for Pathology, Imperial Colleger.goldin@imperial.ac.uk

How big is the problem?

WHO. European Status Report on Alcohol and Health: World Health Organization. Regional Office for Europe; 2010.

EASL Clinical Practice Guidelines2012

Hepatology 2016:64;19-22

Prevalence of NAFLD

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Natural History of NAFLD

Hepatology 2016:64;19-22

Advanced liver fibrosis in NAFLD

0.2% of American adults had NASH-related cirrhosis in the 2002-2012 group compared to 0.1% in the 1999-2002 group.The prevalence of advanced fibrosis increased from 1 to 2%.Over 4 million individuals in 2010 had NAFLD-associated advanced fibrosis.Over 400, 000 had cirrhosis

Am J Gastroenterol 2017;112:581-587.

Prognosis of NAFLD

NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The histological activity was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality.

Hepatology 2015:61:1547-54.

NASH and cardiovascular disease

NAFLD is an independent risk factor for atherosclerosis and cardiovascular disease

• Fatty liver as an independent predictor of early carotid atherosclerosis: results from a large transversal and long-term follow-up J Hepatol, 65 (2016), pp. 95–102

• Nonalcoholic fatty liver disease and vascular function: cross-sectional analysis in the Framingham heart study Arterioscler Thromb Vasc Biol, 35 (2015), pp. 1284–1291

World J Gastroenterol 2016 ;22: 9674-9693

One disease or two?

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"If it talks like a duck and walks like a duck, it's a duck!"

NASHASH

Nature: Nurture:

Alcohol production in NASH• Dysbiosis might increase intestinal ethanol production; for example,

1 g of Escherichia coli can produce 0.8 g of ethanol per hour in anaerobic conditions

• The ob/ob mice that develop NASH have higher early-morning breath alcohol content compared with their lean littermates

• Elevated blood ethanol levels have also been observed in patients with NASH

• Ethanol produced in the gut might contribute to liver injury by increasing intestinal permeability and portal LPS levels

Nature Reviews Gastroenterology & Hepatology 2016;13:412–425

Is Moderate Alcohol Use in Nonalcoholic Fatty Liver Disease Good or Bad? • Insufficient studies have assessed the association of

moderate alcohol use with cardiovascular outcomes. • There was a positive association between moderate alcohol

use and decreased NASH and fibrosis.• However, heavy episodic drinking may accelerate fibrosis

progression and moderate alcohol use may increase the risk of hepatocellular carcinoma in patients with advanced fibrosis

Hepatology2017:65;2090-2099

Pathology

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Histological Scoringsevere (>66%)

Image analysis:Fat percentage: 55.9%

Percentage errors vary from 0 to 2.8%, between annotation and automatic software.

Information 2017, 8, 36

Fat

The use of guideline images to improve histologicalestimation of hepatic steatosis.

Liver Int. 2014 Oct;34(9):1414-27

Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.

Mod Pathol. 2005 Jul;18(7):912-6.

Our fully automated software uses low-resolution images (2x) widely available and shows excellent correlation with experts’ annotation.

Ballooning and lobular inflammation grading. B) Normal hepatocytes, ballooning, grade 0. Cytoplasm is pink and granular and liver cells have sharp angles. H&E, X 40. (C) Ballooning, grade 1. Hepatocytes have rounded contours with clear reticular cytoplasm. Size is quite similarto that of normal hepatocytes, H&E, X 40. (D) Ballooning, grade 2. Cells are rounded with clear cytoplasm and twice as large as normal hepatocytes (star), H&E, X 40

Hepatology. 2012 ;56 :1751-9

Extending the Ballooning Score Beyond 2: A Proposal for a New Balloon Score (AASLD 2015)• Compared to cases without ballooning, non-classical

ballooning cases had more severe histology• Compared to non-classical ballooning cases, classical

ballooning cases had more severe histology• Severe ballooning cases differed from non-severe ballooning

in that they had more severe histology

Recognising ballooned hepatocytes I

Adv Anat Pathol 2017;24:99–109

• ubiquitin• p62

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Recognisng ballooning II

Human Pathology 2012; 43: 790–800

Double staining with: • red chromagen-tagged

ubiquitin and • brown chromagen-

tagged K8/18 antibody.

Distinction of alcoholic liver disease from non-alcoholic liver disease

• Clinical featuresAlcohol intake: less than 10g/day in women, 20 g/day in men

• Blood tests• Imaging• Histology

Differences between ASH and NASH• The following are commoner in ASH: diffuse microvesicular steatosis, cholestasis,

neutrophilic satellitosis of Mallory–Denk body‐containing balloon cells, a dense networks of perisinusoidal fibrosis

• Only ASH shows a significant incidence of veno‐occlusive lesions and sclerosinghyaline necrosis.

• The following is commoner in NASH: nuclear vacuolation• Only NASH has the unique zone 1 borderline injury pattern of pediatric fatty liver

disease

Clinical Dilemmas in NAFLD Elsevier 2016 p 72, Histopathology. 2010 Mar;56(4):426-9.

Although distinguishing NASH from NAFLD may still have relevance for clinical practice, we suggest that using this binary classification in clinical research is somewhat artificial.

Gastroenterology2015;149:1305-8

Case LM1 Age 46, MaleNAFLD BMI >32, DM on insulin. NASH? Degree of fibrosis.

Suggested scoring: Majority diagnosis was steatohepatitis, but 21 steatosis, so less than 80% consensus. For full marks, need fatty liver disease, and some comment that this is consistent with the clinical history of metabolic syndrome.

Non-Alcoholic Liver Disease

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Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame

Dig Dis Sci 2016; 61:1325–1336

Causes of NAFLD

BioMed Research International2015 http://dx.doi.org/10.1155/2015/168905

Nonobese Fatty Liver Disease

• NAFLD can be found in nonobese individuals. • Although NAFLD this has been reported in children and adults of all

ethnicities, more frequently in Asians.• The prevalence of nonalcoholic steatohepatitis does not differ

significantly between nonobese and obese patients. • Associated with : visceral obesity, high fructose and cholesterol

intake, and genetic risk factors (e.g., palatin-like phospholipase domain-containing 3).

Clinical Gastroenterology and Hepatology 2017;15:474–485

Modern Pathology 2017; 30,: 834–842

• Roux-en-Y gastric bypass in 4• starvation-like dieting or hypoalbuminemia in

2

Aggressive non-alcoholic steatohepatitis following rapid weight loss and/or malnutrition

Scoring NAFLD

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NAFLD Activity Score

Steatosis grade Lobular inflammation Hepatocellular ballooning

0: <5% 0: None 0: None

1: 5-33% 1:<2 foci/20x field 1: Mild, few

2: 34-66% 2: 2-4 foci/20x field 2: Moderate – marked,

3: >66% 3: >4 foci/20x field many

NAFLD activity score (NAS): 0-8Steatosis (0-3) + Lobular Inflammation

(0-3) + Ballooning (0-2)

The NAS and The Histopathologic Diagnosis in NAFLD: Distinct Clinicopathologic Meanings. Hepatology. 2011 Mar; 53(3): 810–820.

The NAS and the Histopathologic Diagnosis in NAFLD: Distinct Clinicopathologic Meanings. Hepatology. 2011 Mar; 53(3): 810–820.

Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease

HepatologyVolume 60, Issue 2, pages 565-575, 26 JUN 2014 DOI: 10.1002/hep.27173http://onlinelibrary.wiley.com/doi/10.1002/hep.27173/full#hep27173-fig-0001

Improves interobserver variation.

Hepatology. 2014; 60: 565–575

Does the SAF predict natural history?

After adjustment for fibrosis, the SAF score was not associated with increased mortality in NAFLD.

Scand J Gastroenterol. 2017;52 :87-91

Factors determining the prognosis of NAFLD

• “Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.”

Gastroenterology 2015; 149: 389–397

Progression of fibrosis in NAFLD• A meta-analysis of studies of paired liver biopsy studies.• The annual fibrosis progression rate in patients with NAFL who had

stage 0 fibrosis at baseline was 0.07 stages compared with 0.14 stages in patients with NASH.

• These findings correspond to 1 stage of progression over 14.3 years for patients with NAFLD and 7.1 years for patients with NASH.

• Liver fibrosis progresses in patients with NAFLD and NASH.

.Clinical Gastroenterology and Hepatology 2015;13:643–654

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Liver Histology and Clinical Trials for Nonalcoholic Steatohepatitis

• Fibrosis is a more powerful predictor of long-term outcome than other histologic features

• Fibrosis is easy to assess histologically and highly reproducible between pathologists. It is a robust criterion provided that the biopsy is adequate

• Fibrosis regression might, therefore, be the best surrogate marker for assessing benefit of a drug.

Gastroenterology 2015;149:1305-8

Alcoholic Liver Disease

Am J Pathol 2016; 186: 748e760

Animal Models of Alcoholic Liver Disease EASL Clinical Practice Guidelines:Indications for liver biopsy

• Presence of ALD can be suspected based on clinical, biological, and ultrasound parameters. Nevertheless, histology is required for confirmation of the diagnosis and evaluation of the severity of ALD

(Recommendation B1)• Liver biopsy should be considered in patients

with aggressive forms of ALD requiring specific interventions in patients with cofactors suspected to contribute to liver disease and in the setting of clinical studies.

(Recommendation B1)• Although the presence of ASH can be suspected

on clinical and biochemical grounds, a definite diagnosis of ASH requires a liver biopsy

(Recommendation A1)

J Hepatol. 2012;57:399–420.

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

Gastroenterology. 2014; 14: 1231–1239.

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Histopathological agreement:Kappa values

0.65 for fibrosis0.86 for bilirubinostasis0.60 for neutrophil infiltration and 0.46 for megamitochondria.

STOPAH Histology

• Liver histology remains a useful tool in patients presenting with features of alcoholic hepatitis but with diagnostic uncertainty.

• Where the diagnosis is made clinically with confidence histology will identify 13 % of patients with alternative diagnoses, predominantly that of inactive cirrhosis.

• Provides independent validation of the AHSS

N Engl J Med. 2015;372:1619-28

Prognosis of Alcoholic Liver Disease 192 consecutive patients with biopsy proven ALD: In early/compensated ALD, severe fibrosis stage was associated with significantly lower 10-year survival rateIn decompensated ALD patients, a combination of histological (pericellular fibrosis), clinical (sex) and biochemical (bilirubin and INR) parameters were predictive of liver related death. Alcohol abstinence was associated with improved survival in both early/compensated and decompensated ALD.

J Hepatol 2017; 66; 610-618.

Fat and liver tumours HCC in patients with NAFLD

• “In noncirrhotic HCC patients, histological steatosis was frequently present, whereas overt steatohepatitis did not occur. ”

Eur J Gastroenterol Hepatol. 2016;28:955-62.

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NAFLD-HCC

• could arise also in the absence of cirrhosis• more often detected at a later tumor stage

Hepatology 2016;63:827–838

Steatotic HCC• Steatotic HCC is a common histological

variant of HCC (21.1%) with distinct association with underlying fatty liver, steatohepatitis and metabolic risks.

• Despite more favourable baseline tumourfeatures, it was associated with late tumourrelapse.

Histopathology 2016; 69:971-984.

Steatotic adenomas

Gastroenterology 2017;152:880–894

Steatotic focal nodular hyperplasia 33 cases with features typical of of FNH and fatty change. Steatohepatitis like changes were focally present in 54%.

Thick plates > 3 cells were focally found in 42%; rosettes in 70%. Am J Surg Path 2017;41:277-81