Please Silence Your Cell Phones Meeting (CM)/CM10-15/DDx Fatty Liver...• Ranges from hepatocytes...

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The USCAP requires that anyone in a position to influence or control the content of all CME activities disclose any relevant relationship(s) which they or their spouse/partner have,

or have had within the past 12 months with a commercial interest(s) [or the products or services of a commercial interest] that relate to the content of this educational activity and create a conflict of interest. Complete disclosure information is maintained in the USCAP

office and has been reviewed by the CME Advisory Committee.

Dr. (Elizabeth Brunt) declares consulting work for Rottapharm.

Ddx of Fatty Liver Disease:

Not the Usual Culprits

Elizabeth M. Brunt

Department of Pathology and Immunology

Hans Popper HepatopathologyCompanion Society

March 22, 2015

Outline• Why is this important to discuss?

– Epidemiology of fatty liver

• What are the usual culprits– IR– Alcohol

• What are the Not-So-Usual culprits?

What is NAFLD, 2015

• Fatty infiltration– ? Tumoral infiltrates?– ? Primary or Mets?

• Simple steatosis– What is it about metabolic pathways

that result in triglyceride accumulation is simple?

• Puhleeeeezzzz don’t say:

What is NAFLD, 2015

• A spectrum of liver diseases with macrofat– NOT related to excess

alcohol intake

• Ranges from hepatocytes with >5% macrovesicularsteatosis– Large and small droplet

• PLUS inflammation– Lobular +/- portal

• PLUS hepatocyte injury (ballooning)

• +/- fibrosis in varying patterns of distribution

What is NAFLD, 2015

• A spectrum of liver diseases with macrofat– NOT related to excess

alcohol intake

• +/- liver cell injury• +/- cirrhosis• +/- liver carcinoma

– HCC– Any primary liver carcinoma

with or without cirrhosis

• Ranges from hepatocytes with >5% macrovesicularsteatosis– Large and small droplet

• PLUS inflammation– Lobular +/- portal

• PLUS hepatocyte injury (ballooning)

• +/- fibrosis in varying patterns of distribution

NAFLD, 2015: Epidemiology• Purists: require biopsy for liver fat >5%, NASH• Imagers: trust various modalities

– Ultrasound– CT – MR

• Proton MR spectroscopy (1H-MRS)• PDFF: standardized MR-based biomarker of tissue fat

concentration; uses MRS or MRI (Reeder, Hu, Sirlin*)

• Reviewers: gov-based population studies• Realists:

*JMRI 2012; 36:1011-1014

NAFLD, 2015: EpidemiologyPurists

• Outpatients to Brooke Army Medical Base400

outptsenrolled

328 completed

US

156 pos: 48%

NAFLD

LIVER BIOPSY:

5 were NORMAL

22 refused liver biopsy

Williams, et al. Gastroenterol 2011;140:124-131


• Outpatients to Brooke Army Medical Base48% with

NAFLD

Hispanics (58%) > Caucasians (44% ) > African Americans (35%)

Men: 59%Obese: 68%Older



• Outpatients to Brooke Army Medical Base48% with NAFLD

NASH

by bx: n=40

12.2% total

29.9% US pos

Fibrosis St 2-4:

2.7% of cohort

NASH Prevalence amongst all 328:

12.2%

Men 65%Higher BMI, IR, ALT, AST

Hispanics (19.4%) > African Americans (13.5%) >Caucasians (9.7%)



• Outpatients to Brooke Army Medical Base48% with

NAFLD

NASH by bx: 29.9%

Fibrosis St 2-4:

2.7% of cohort

54 Diabetics

74% had NAFLD

22% had NASH

NASH Prevalence amongst all 328:

12.2%

Men 65%Higher BMI, IR, ALT, AST

Hispanics (19.4%) > African Americans (13.5%) >Caucasians (9.7%)


0

50

100

150

200

250

300

350

400

450

TotalEnrolled

CompletedQ-R, US

NAFLD NASH

OutPatientColumn1Psoriasis#REF!


Williams, et al. Gastroenterol 2011;140:124-131; Roberts, et al. Aliment Pharm Therap 2015;41:293-300.

0102030405060708090

OutPtPsoriasis


%

Williams, et al. Gastroenterol 2011;140:124-131; Roberts, et al. Aliment Pharm Therap 2015;41:293-300.

NAFLD, 2015: EpidemiologyImagers: US

• Ultrasound– Noninvasive– Least expensive, most

available– Low sensitivity, specificity

• Difficult to ddx steatosis, fibrosis

– Machine and operator dependent

– Doesn’t reliably detect steatosis < 30%

• In United States, prevalence of NAFLD by US is…17-51% *(yikes!)– Obesity: 90%*

– T2DM: 69%**

– Hispanic men: 45%***

Chalasani, Hepatology 2012 Vernon, Alimen Pharm Therap 2011 Browning, Hepatology 2004

• Quantitative US– One study published

to date; from UCSD– Comparator group

was MRI-PDFF– 2 year study of 204

subjects randomized to training and validation sets

– NAFLD in each group was 69%

• Back scatter calculation of QUS v MRI-PDFF

Spearman P 0.8, p<0.0001AUC (training): 0.98

• QUS is inexpensive, algorithms in place to reduce operator, machine error sources

• Can be done on any US machine

NAFLD, 2015: EpidemiologyImagers: QUS

Lin et al, Clin Gastro Hepatol 2015, epub accepted manuscript

Training Validation

Sensitivity 93% 87%Specificity 97% 91%Pos Predict Value 99% 95%Neg Predict Value 86% 76%

• Noninvasive, but involves radiation

• 100% specificity at >30% steatosis, but difficult to quantify steatosis

NAFLD, 2015: EpidemiologyImagers: CT

NAFLD, 2015: EpidemiologyImagers: 1H-MR Spectroscopy

Urban population, Dallas County 34% prevalence

0%

10%

20%

30%

40%

50%

60%

Population

IHTG >5.5%

Browning, et al. Hepatology 2004;40:1387-1395.

(2,240)

NAFLD, 2015: EpidemiologyImagers: 1H-MR Spectroscopy

Urban population, Dallas County 34% prevalence

0%

10%

20%

30%

40%

50%

60%

Population

IHTG >5.5%

Browning, et al. Hepatology 2004;40:1387-1395.

(2,240)

0%10%20%30%40%50%60%70%80%90%

Population

IHTG >5.5%

Wong, et al. Gut 2012;61:409-415

(900)

Urban population, Hong Kong 27.3% prevalence

• Proton-density fat fraction – maps the entire liver– correlates well in adults

for quantitative measurements of hepatic steatosis

– PDFF was better than biopsy for steatosis over time in clinical trials1

– Costly– Not widely available

NAFLD, 2015: EpidemiologyImagers: MRI-PDFF

1Noureddin, et al. Hepatology 2013; 58:1930-1940

• ? “American Exceptionalism”

• Genetic, epigenetic

• Environmental

NAFLD, 2015: EpidemiologyPopulation

Loomba et al, Nat Rev Gastroenterol Hepatol 2013; 10:686-690.

Reprinted with permission from TheimePublishing, Lic #3560830451577.

Usual Culprits

• Insulin Resistance • Alcohol (? How, how much and in whom)

• “ 2 doses/day”

• Men: >60g/d; Women: >10-20g/d

Usual Culprits

• Insulin Resistance • Alcohol (? How, how much & in whom)

• “ 2 doses/day”

• Men: >60g/d; Women: >10-20g/d

FLD; Cirrh; HCC

Hyperlipidemia

Truncal Obesity

Not-So-Usual Culprits

• Disordered Gut• Lipodystrophic Syndromes• Medications• Storage Disorders• Viral Hepatitis• The W’s

Not-So-Usual Culprits: Disordered (malabsorptive) GutThe Normal Gut: from the perspective of a hepatopathologist!

• Fat accumulates in the liver at both ends of the nutritional spectrum…– Over (obesity)– Under (protein/calorie)

malnutrition

Not-So-Usual Culprits: Disordered (malabsorptive) Gut

Reilly, et al. J Hepatol 2015; http://dx.doi.org/10.1016/j.jhep.2015.01.013


Kummen, et al. Best Pract Res Clin Gastroenterol 2013;27:531-542.; reprinted with permission.


Kummen, et al. Best Pract Res Clin Gastroenterol 2013;27:531-542; reprinted with permission.

• Inflammatory Bowel Disease: 5-10% elev TA’s– Associations in order of frequency PSC, NAFLD,

cholelithiasis, AIH, PBC

Kummen et al. Best Pract Res Clin Gastroenterol 2013;27:531-542; Vo et al. JPGN, 2014;59:288-299.


• Inflammatory Bowel Disease: 5-10% elev TA’s– Associations in order of frequency PSC, NAFLD,

cholelithiasis, AIH, PBC…and…• AIH-PSC overlap• DILI: MTX and steroids • Granulomatous liver disease• Abscess• Budd-Chiari or portal vein thrombosis• Hepatic amyloidosis• CCa

Kummen, et al. Best Pract Res Clin Gastroenterol 2013;27:531-542 ; Vo, et al. JPGN, 2014;59:288-299.


IBD and Steatosis/SH• UC and NAFLD: 1st described in 1873• Up to 36-50% of all IBD pts have steatosis;

hepatomegaly is unusual– Toxemia, malnutrition, prednisone, parenteral

nutrition– Related to severity of colonic involvement– May persist after colectomy

De Boer et al, Scand J Gastro 2008; 43:604-608; Kummen, et al. Best Pract Res Clin Gastroenterol 2013;27:531-542.

• Celiac Disease– Found in 1% of European and NA populations

10% of subjects with unexplained liver test elevations 3.5% of NAFLD subjects1

– “Celiac hepatitis” (after r/o AIH, PBC, PSC, GSRH)• mild steatosis, KC hyperplasia, mild mononuclear infiltrate, mild fibrosis; reversible with diet

(Maggiore, 2003)

– Possible causes of steatosis/steatohepatitis in CD• Malabsorption/chronic deficiency of lipotropic factor• Increased intestinal permeability, similar to SIBO;

increased translocation of bacterial toxin, other ags to liver– Increased risk of NAFLD in newly diagnosed Celiac2

• Highest in first year after Celiac dx, but can remain • Most commonly in children with Celiac


1Abenavoli, et al. Minerva Gastroenterol Dietol 2013;59:89-95; 2Reilly, J Hepatol 2015; http://dx.doi.org/10.1016/j.jhep.2015.01.013

• Cystic Fibrosis: liver disease is now the most important nonpulmonary COD in CF

• While we usually think of the “focal biliary cirrhosis” in CF…

• “the most prevalent liver histopathologicfinding is … steatosis…noted in up to 60% of subjects”. – Attributed to overall malnutrition and CF related

deficiencies: EFA, carnitine, choline


Vo et al. JPGN, 2014;59:288-299.

Not-So-Usual Culprits: Lipodystrophy

• Rare syndromes associated with IR-T2DM, dyslipidemia and NAFLD/NASH; some also assoc with premature aging

• Atrophy of body fat– Partial or generalized– Congenital or acquired

• Impairment of adipogenesis; deregulation of adipocyte droplets (perilipins)

• Leptin deficiency, PPAR dysfunction; nuclear envelope protein (lamin-B) dysfunction

• One of best known associations is ART in HIV– Partial lipodystrophy and IR

Guenantin et al. Semin Cell Dev Bio 2014;29:148-157.

Not-So-Usual Culprits: Medications

Steatosis• Corticosteroids

– Steatosis, glycogenosis– SH: exacerbation > de novo– Rarely implicated in progressive FLD

• Methotrexate– Steatosis, hepatocellular unrest,

nuclear pleomorphism– Beware: SH and/or Z3 psf may mean

concurrent Met Syn or alcohol exposure

– Fibrosis in MTX begins portal, periportal; can lead to cirrhosis

– Fibrosis most often occurs in presence of concurrent co-factors: Met Synd, DM, EtOH

Steatohepatitis• Tamoxifen

– Fatty liver: up to 1/3 of users; SH less common

– Fibrosis occurs; cirrhosis > 3-5 yrs use

– Steatosis is more common in W with elev BMI, but not related to EtOH; drug does not cause wt gain

• Amiodarone– Usually ALT, AST ( = ) elev but can

be cholestatic– Can see ballooning, MDB without

steatosis– Can lead to cirrhosis– Slow to accrue, slow to dissipate

from lipids in cell membranesLiverTox.NIH

Medications: Amiodarone*DDx is usually Heart Failure

The many faces of amiodarone: phospholipidosis; MDB; cholestrosettes; fibrosis

Steatosis is rare; psf, fibrosis are not

• LAL deficiency: chol esters and TG cannot be removed from hepatocytes and Kupffer cells

Not-So-Usual Culprits: Storage Disorders

Review: 135 Cases in LiteratureJ Hepatol 2013;58:1230-1243

LAMP-1 and cathepsin D IHC for lysosome staining

Cathepsin D in -oxidation defect Steatosis, Chol in EM of CESD case

Reprinted with permission from Elsevier

• LAL deficiency: Wolman and CESD– Autosomal recessive; LIPA mutations ( > 40); trans-ethnic

• WD is RARE and fatal by 3-4 mos old– CESD is a spectrum depending on LAL activity

• Estimated to affect ~ 1/40,000; considered underestimate• Can present in infancy, childhood or up to mid-late adult• USUALLY PRESENTS AS FIBROTIC LIVER DISEASE

WITH FAT…DDX IS NAFLD/NASH• HSM, type IIb hyperlipoproteinemia (elev serum LDL chol, TG,

normal or low HDL chol)• Liver transplant or liver failure or accel ASVD early demise

Not-So-Usual Culprits: Storage Disorders

Bernstein et al. J Hepatol 2013;58:1230-1243.

Not-So-Usual Culprits: Viral HepatitisViral v Metabolic Steatosis

• HCV – Zone 1: Virus; Zone 3 steatosis +/- perisinusoidal fibrosis: Host– Gt 1, 4, other non-3: incite IR = METABOLIC STEATOSIS– Gt 3: core protein causes steatosis = VIRAL STEATOSIS– Concurrence: Met Syn +/- ALD…

• ballooning, MDB, satellitosis, sinusoidal fibrosis

– Coexistent ALD increases speed of progression

Negro, J Hepatol 2014; 61:S69-S78


• HCV – Zone 1: Virus; Zone 3 steatosis +/- perisinusoidal fibrosis: Host– Gt 1, 4, other non-3: incite IR = METABOLIC STEATOSIS

– Gt 3: core protein causes steatosis = VIRAL STEATOSIS

– Concurrence: Met Syn +/- ALD…• ballooning, MDB, satellitosis, sinusoidal fibrosis

– Coexistent ALD increases speed of progression

Negro, J Hepatol 2014; 61:S69-S78


Viral Steatosis Metabolic Steatosis

HCV GT 3 GT non-3

Response to IFN- NO EFFECT REDUCES

Fibrosis NO EFFECT ACCELERATES

HCC Risk Likely but not studied YES

Modified from Negro, J Hepatol; 2014: S69-S78


Viral Steatosis Metabolic Steatosis

HCV GT 3 GT non-3

Response to IFN- NO EFFECT REDUCES

Fibrosis NO EFFECT ACCELERATES

HCC Risk Likely but not studied YES

Modified from Negro, J Hepatol; 2014: S69-S78 ; Cheng et al. J Viral Hep 2014;21:1-8.

What do we know in the new era of DAA viral therapy?

-IR is less relevant to outcomes of DAA’s

-statins may have deleterious adverse side effects


• HCV – Zone 1: Virus; Zone 3 steatosis +/- perisinusoidal fibrosis: Host– Gt 1, 4: incite IR = METABOLIC STEATOSIS– Gt 3: core protein causes steatosis = VIRAL STEATOSIS– Concurrence: Met Syn +/- ALD…ballooning, MDB, satellitosis, sinusoidal fibrosis– Coexistent ALD increases speed of progression

• HBV– Meta-analysis of 21 studies, > 4,000 patients2

– Present in up to 1/3 of patients, but usually mild, sometimes moderate; ranged 14-70%

– Most common assoc: male, older, Met Syn features, alcohol; NO VIRAL FACTORS

– ? Protective effect of virus on steatosis– No effect on histologic progression

• Labrea Hepatitis (acute HDV)– Coinfection/superinfection with HBV; South America– Microvesicular or macrovesicular steatosis

Negro, J Hepatol 2014; 61:S69-S78; 2Machado et al. JGH 2011;21:1361-1367.

Not-So-Usual Culprits: The W’s

Weber-Christian Disease with Hepatic Involvement

• Systemic illness• Lobular panniculitis of subQ

fat, recurring febrile episodes• Unusual for liver to be

involved….but reported – Presents with transaminitis,

“fatty liver”– LOOKS LIKE SH ON BX

• Treatment is steroid therapy, other immunosuppression

Wilson Disease

Not-So-Usual Culprits: The W’s

Weber-Christian Disease with Hepatic Involvement

• Systemic illness• Lobular panniculitis of subQ

fat, recurring febrile episodes• Unusual for liver to be

involved….but reported – Presents with transaminitis,

“fatty liver”– LOOKS LIKE SH ON BX

• Treatment is steroid therapy, other immunosuppression

Wilson Disease

• The “lupus” of liver disease but can have steatosis as a major finding

Copper measurement: 1430 ug/g dry weight (n = 10-35 ug/g)

(NA)FLD/(NA)SH: Culprits to know

Significant

• IR/Alcohol–T2DM

• Viral Hepatitis C; B+D• Malnutrition

– IBD– Celiac Sprue

• CESD• Certain medications

– Tamoxifen– Amiodarone– Methotrexate– Steroids

• Wilson Disease• Weber-Christian Disease

+/- Obesity, Metabolic Syndrome


Significant• IR/Alcohol

– T2DM

• Viral Hepatitis C; B+D

• Malnutrition– IBD– Celiac Sprue

• CESD

• Certain medications– Tamoxifen– Amiodarone– Methotrexate– Steroids



Significant

• IR/Alcohol– T2DM

• Viral Hepatitis C; B+D

• Malnutrition– IBD– Celiac Sprue

• CESD

• Certain medications– Tamoxifen– Amiodarone– Methotrexate– Steroids


Macro, large/small

True Micro

KC Steatosis

Ballo-oning, MDB

PSF may be clue

Risk of HCC, Cirrh or NON-C

Met Synd + + ++ + ++ ++

ALD + + ++ + ++ +; +/-

Viral Hep + * * ++

Malnutrit-tion

+ *

CESD small ++

Tamoxifen + + + +

Amiodar +/- ++ VOO

Methotrexate

+ ++ Zone 1

Steroids +

WD + + ++ +

WCD + MDB +* Concurrent NASH/ASH



– T2DM– Psoriasis






• Metabolic disorders– Galactosemia– GSD I and III– Hereditary Fructose

Intolerance– Nieman Pick C– Tyrosinemia

• Cystic Fibrosis• Heat Stroke• Ischemic liver

Steatosis and elevated TA’s



– T2DM– Psoriasis






Steatosis and elevated TA’s

• Metabolic disorders– Galactosemia– GSD I and III– Hereditary Fructose

Intolerance– Nieman Pick C– Tyrosinemia

• Cystic Fibrosis• Heat Stroke• Ischemic liver

Mitochondriopathies

• Clinical settings are very different

• Acute liver failure, SIDS

• Reye’s• Urea cycle

defects• AFLP

• Microvesicularsteatosis

Please go to the USCAP website to complete your Evaluation of

the course and claim CME and/or SAMs Credits.

Thank You!

Fatty Liver Disease

• Can a patient have more than one process that results in the same/similar microscopic features?– HCV + NAFLD/NASH or HCV + ALD/ASH

• Patients with MetSynd or ALD

• What are criteria for suggesting/diagnosing such?– In addition to portal-based features of …HCV…

• Zone 3 PSF1

• Zone 3 ballooning2

• Does harmful lipid overload always have to be in hepatocytes? – Vit A toxicity: Stellate cell loading…psf

1Brunt et al. Mod Pathol 2003;16:49-56; 2Bedossa et al. Hepatology 2007;46:380-387.

HCV (+ SH)

HCV (+ SH)Stellate Cell Hypertrophy

Usual Culprits of Fat in Liver

• Insulin Resistance • Obese, BMI < 40, non-DM, no

other serious complic• Metabolically Normal Obese

– < 5.6% IHTG (defn)– Protected from all metabolic

consequences of weight gain of ~ 6%

– Lipogenic pathways in fat stores

• Metabolically Abnormal Obese– > 5.6% IHTG; all parameters

worsened with similar weight gain– No adaptation by fat stores

Fabrinni, et al. JCI 2015; doi:10.1172/JCI78425.

Which statement below is true????

IR = Obesity = Fatty Liver

Obesity = IR = Fatty Liver

Fatty Liver = IR = Obesity

Fatty Liver = Obesity = IR


• Insulin Resistance • Obese, BMI < 40, non-DM, no

other serious complic• Metabolically Normal Obese

– < 5.6% IHTG (defn)– Protected from all metabolic

consequences of weight gain of ~ 6%


• Metabolically Abnormal Obese– > 5.6% IHTG; all parameters

worsened with similar weight gain– No adaptation by fat stores


Which statement below is true????

IR = Obesity = Fatty Liver

Obesity = IR = Fatty Liver

Fatty Liver = IR = Obesity

Fatty Liver = Obesity = IR

None are completely true!


• Insulin Resistance • Obese, BMI < 40, non-

DM, no other serious complic

• Metabolically Normal Obese– < 5.6% IHTG (defn)

• Metabolically Abnormal Obese– > 5.6% IHTG

• MetN – O vs MetAbn – O

– 6% wt gain, fast food diets

– Protected from all metabolic consequences of weight gain of ~ 6%


– All parameters worsened with similar weight gain

– No adaptation by fat stores


Please Silence Your Cell Phones Meeting (CM)/CM10-15/DDx Fatty Liver...• Ranges from hepatocytes...

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