Please Silence Your Cell Phones Meeting (CM)/CM10-15/DDx Fatty Liver...• Ranges from hepatocytes...
Transcript of Please Silence Your Cell Phones Meeting (CM)/CM10-15/DDx Fatty Liver...• Ranges from hepatocytes...
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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
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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
NAFLD, 2015: EpidemiologyPurists
• Outpatients to Brooke Army Medical Base48% with
NAFLD
Hispanics (58%) > Caucasians (44% ) > African Americans (35%)
Men: 59%Obese: 68%Older
Williams, et al. Gastroenterol 2011;140:124-131
NAFLD, 2015: EpidemiologyPurists
• 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%)
Williams, et al. Gastroenterol 2011;140:124-131
NAFLD, 2015: EpidemiologyPurists
• 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%)
Williams, et al. Gastroenterol 2011;140:124-131
0
50
100
150
200
250
300
350
400
450
TotalEnrolled
CompletedQ-R, US
NAFLD NASH
OutPatientColumn1Psoriasis#REF!
NAFLD, 2015: EpidemiologyPurists
Williams, et al. Gastroenterol 2011;140:124-131; Roberts, et al. Aliment Pharm Therap 2015;41:293-300.
0102030405060708090
OutPtPsoriasis
NAFLD, 2015: EpidemiologyPurists
%
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
Not-So-Usual Culprits: Disordered (malabsorptive) Gut
Kummen, et al. Best Pract Res Clin Gastroenterol 2013;27:531-542.; reprinted with permission.
Not-So-Usual Culprits: Disordered (malabsorptive) Gut
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.
Not-So-Usual Culprits: Disordered (malabsorptive) Gut
• 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.
Not-So-Usual Culprits: Disordered (malabsorptive) Gut
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
Not-So-Usual Culprits: Disordered (malabsorptive) Gut
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
Not-So-Usual Culprits: Disordered (malabsorptive) Gut
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
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
Not-So-Usual Culprits: Viral HepatitisViral v Metabolic Steatosis
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
Not-So-Usual Culprits: Viral HepatitisViral v Metabolic Steatosis
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
Not-So-Usual Culprits: Viral HepatitisViral v Metabolic Steatosis
• 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
(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
(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
(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
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
(NA)FLD/(NA)SH: Culprits to know
Significant• IR/Alcohol
– T2DM– Psoriasis
• Viral Hepatitis C; B+D• Malnutrition
– IBD– Celiac Sprue
• CESD• Certain medications
– Tamoxifen– Amiodarone– Methotrexate– Steroids
• Wilson Disease• Weber-Christian Disease
• 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
(NA)FLD/(NA)SH: Culprits to know
Significant• IR/Alcohol
– T2DM– Psoriasis
• Viral Hepatitis C; B+D• Malnutrition
– IBD– Celiac Sprue
• CESD• Certain medications
– Tamoxifen– Amiodarone– Methotrexate– Steroids
• Wilson Disease• Weber-Christian Disease
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
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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.
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
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
None are completely true!
Usual Culprits of Fat in Liver
• 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%
– Lipogenic pathways in fat stores
– All parameters worsened with similar weight gain
– No adaptation by fat stores
Fabrinni, et al. JCI 2015; doi:10.1172/JCI78425.