When you have eliminated the

impossible: The Primary Care

Sleuths Guide to Approaching
Transaminitis
Corinne Wentworth-Kotara
Liver Consultants of Texas
Baylor University Medical Center at
Dallas
 Disclosures
Speakers bureau Bayer/Onxy, Genentech, Gilead
Sciences, Merck, Vertex
Consultant Merck
Advisory board Merck, Vertex

This presentation will not contain off label use/

recommendations
 Objectives
Describe the patient population at risk for chronic
liver disease
Define historical elements suggestive of CLD
Describe physical findings suggestive of CLD
Identify the appropriate primary care evaluation
of transaminititis
Describe appropriate counseling points for
patients at risk of/with CLD
Define appropriate referral for patients with CLD
 The Usual Suspects
Chronic hepatitis C
NAFLD/NASH liver
Alcoholic liver disease
Autoimmune Hepatitis
Chronic hepatitis B
Hemochromatosis
Others: Wilsons, drug injury, PBC, PSC, alpha-
1 antitrypsin deficiency
 Approach to the CLD Patient
Listen for clues - fever, chills,
myalgias, arthralgias, abdominal
pain, jaundice, dark urine, acholic
stools, melana, hematochezia,
abdominal bloating/swelling,
peripheral edema, complaints of
confusion/forgetfulness
Fatigue is a common, non-specific
complaint
Smokers w/ acute HAV may report not
wanting to smoke
 Approach to the CLD Patient
Identify risk factors/behavioral patterns
Percutaneous/blood exposures/tattoos
Alcohol use
Sexual practices
Emigration/foreign travel
Family history of liver disease
Observe for physical findings
Hepatomegaly, splenomegaly, spider angioma,
palmer erythema, icterus, jaundice, ascites,
peripheral edema, caput medusa
 Collect the Evidence
HFP/CMP
PT/INR
CBC with platelets
TSH
Serological testing for:
Viral hepatitis
Autoimmune markers
Iron studies
Imaging (US/MRI/CT)
 Bag of Tricks (Specific Labs)
Viral serologies for HAV/HBV/HCV
ANA, AMA, ASMA for autoimmune causes
Iron studies with ferritin for hemachromatosis
HFE mutation analysis (genetic testing)
Ceruloplasmin for Wilsons
 Common Transaminitis Patterns
AST ALT Comment
HBV Normal to mild Normal to mild HBsAg +, DNA +/-
HCV Normal to mild Normal to mild HCV Ab+, RNA +
NAFL/NASH Normal to mild Normal to mild No alcohol history
ALD Mild to moderate Mild to moderate 2-3:1 ratio
AIH Moderate to Moderate to ANA +
marked marked
Hemochromatosis Normal to mild Normal to mild High iron saturation
& ferritin; elevated
HGB
 The Victim
Col (ret) Mustard is a 59 y/o white male who
presents to establish PCP care
Last saw PCP 9 years ago
Did not return b/c he recommended that test
Denies DM, HTN, COPD, renal
Last real physical after retiring from the army
Works in banking, married, 3 kids, smokes
pack/day, 1 2 drinks at night for many years
Denies blood transfusions, IVDA, tattoos but did try
INC once in college
His only complaints are weight gain and fatigue
 The Crime Scene
BP 143/89, pulse 95, weight 235 lbs, height
511
Anicteric, abdomen protuberant, liver 2-cm
below RCM, no spleen, no LEE, no spiders or
palmer erythema
 The Evidence
AST 49, ALT 74
Alkaline phosphatase 74
Albumin 4.3, total bilirubin 0.7
INR 0.9
Platelets 163,000
TSH 1.67
HBcAb neg, HBsAg neg, HBsAb positive, HAV Ab
positive, HCV Ab positive
Iron studies: Fe , TIBC, saturation 37%, ferritin
ANA, ASMA, & AMA negative
Ultrasound: Hepatomegaly with fatty infiltration
 Confronting the Evidence
Transaminitis
Positive HCV antibody needs further evaluation
HCV RNA and HCV Genotype
Obesity
Alcohol consumption
Immune to hepatitis A and B
Synthetic function is good, but alcohol and
HCV dont mix
 Hepatitis C
Prevalence 1.8%; 4 5 million affected
CDC considering 1-time screen for all baby
boomers
Leading cause for liver transplantation
Accounts for majority of liver cancer
New medications reduce disease progression
and allow for cure
 HCV Treatment Advancements
Genotype 1 Genotype 2 or 3
Standard Interferon (IFN) 6 26% ALT response rate based upon 24 96 weeks of
(<1998) therapy
Std IFN + Ribavirin (RBV) 29 48% HCV RNA response based upon 24 48 weeks
(1998 2001) of therapy in previous nave and relapser patients
Pegylated Interferon (PEG) 18 - 25%; 70% genotype 1; study did not differentiate
(2001 -) between genotypes
PEG + RBV (20012011) 41 44% 70 75%
PEG + RBV + Direct Acting 62 79% Not applicable
Antiviral (DAA) (2011)*

*There are multiple drugs in development for chronic HCV with

goals of 100% efficacy, less toxicity and shorter duration of
therapy
 NAFLD/NASH
10 20% of Americans with NAFLD
2 5 % with NASH
Unknown mechanism but high association
with insulin resistance, DM, HTN, high
cholesterol
Thought interplay between insulin resistance,
release of cytokines and oxidative stress
Not every obese patient has NAFLD/NASH; not
every NAFLD/NASH patient is obese
Obesity Rates in U.S. 2011
 NAFLD/NASH and Weight Loss
Weight loss of 5 10% associated with
improvement in inflammatory scores
No long term studies on fibrosis
Estimated $59 billion spent on weight loss in
2008
Weight loss and maintenance both
problematic adherence is key
 Disposition
Referred to GI/hepatology
Treatment with new medications for HCV
Started weight loss program with dietary
changes and exercise
Alcohol abstinence
Smoking cessation
 Mrs. Peacock
48 y/o white female, sees OB/GYN annually does not
otherwise see PCP
Married, office work, 2 children
Recently saw friend who noted her eyes were yellow
Non-smoker, drinks 8 10 beers on weekend at
social events, none during week and no liquor; no
IVDA, no tattoos, no blood transfusions
She states she feels fine and has no abdominal pain.
She notes fatigue but states she attributed it to age
 The Crime Scene
139/74, pulse 82, weight 214, height 56
Icteric scleras and oropharynx, no spiders or
palmer erythema, +hepatosplenomegaly, no
ascites or masses, +1 edema to bilateral
ankles
 The Evidence
AST 244, ALT 114 Iron studies: Fe 39, TIBC
Alkaline phosphatase 131 105, saturation 37%,
Albumin 3.2, total ferritin 572
bilirubin 7.1 HBcAb neg, HBsAg neg,
Platelets 39,000; MCV HBsAb positive, HAV Ab
107.3 positive, HCV Ab negative
TSH 2.3, INR 1.2 ANA, ASMA, & AMA
negative
Ultrasound:
hepatomegaly with fatty
liver, enlarged spleen, no
ascites
 Confronting the Evidence
AST:ALT ratio 2:1 suggestive of ASH; 3:1 is ASH
Macrocytosis
Splenomegaly and low platelets suggest cirrhosis
Evidence of hepatic decompensation
Abstinence of alcohol improves outcome
Still at risk for decompensation and HCC
Alcohol counseling: beer is alcohol
Nutrition is key to improvement
 Alcoholic Liver Disease (ASH)
Common misconception that alcohol is liquor
onlyit includes wine and beer
Can affect any age or socioeconomic status
Drinkers who achieve abstinence can have
reasonable life expectancy
Drinkers who continue have decreased life
expectancy
Nutrition is key to recovery
 ALD
Spectrum of disease from fatty liver to
hepatitis to cirrhosis
Rate of progression varies
Remains major cause of liver injury
Natural history studies confounded by
presence of other liver diseases (HCV, etc)
Alcohol dependence versus abuse
Diagnosis based upon history and presence of
liver disease
http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/AlcoholicLiverDisease1-2010.pdf
 Outpatient ALD Treatment
Abstinence
If alcoholic hepatitis there is no safe amount
Relapse rates 67 81%
Medications conflicting studies on prednisone,
acamprosate, naltrexone, disulfiram
Counseling +/- antidepressants
Nutrition majority with protein deficiency
Severity correlates with outcome
Aggressively correct
 Disposition
Referred to hepatologist
Initiate abstinence program
AA, D&A, counseling
Acamprosate, antidepressants
Nutritional counseling
Not a transplant candidate if actively drinking
Requires 6 months of documented sobriety
Not a punishment: many recover significant
function after abstinence
 Mrs. White
21 y/o female, well known to practice
Married 1 year, planning family but has
fertility issues/lack of menstrual cycles
PMH: Excessive acne
Notes that she has trouble concentrating and
is more forgetful, extremely fatigued X 6
months, notes LEE and recent 10 pound
weight gain
 The Crime Scene
BP 102/56, pulse 95, weight 165, height 56
Icteric, multiple spider angiomas, no palmer
erythema, +hepatosplenomegaly, mild ascites,
+2 pitting edema to knees
 The Evidence
AST 514, ALT 437
Albumin 2.6, total bilirubin 5.6
Alkaline phosphatase 198
WBC 3.2, HGB 10.8, Plt 46,000
INR 1.6
TSH 0.93
HBcAb neg, HBsAg neg, HBsAb positive, HAV Ab
negative, HCV Ab negative
Iron studies: Fe , TIBC, saturation 37%, ferritin
ANA positive 1:320, speckled pattern, ASMA, &
AMA negative
 Confronting the Evidence
Marked transaminitis and + ANA highly
suggestive
Cirrhosis suggested by low platelets and
physical findings
Evidence of liver decompensation
 Autoimmune Hepatitis
Hepatic inflammation of unknown cause
Environmental triggers, genetic predisposition, &
failure of immune mechanisms considered
Onset insidious and nonspecific to fulminant
Female:male 3.6:1
Diagnosis based on histological features,
elevated globulins (IgG), marked transaminitis
and positive autoimmune markers (ANA)
 Indications for Immunosuppression
Treatment
Absolute
Serum AST 10 fold ULN
Serum AST 5 fold ULN and
c globulin level 2 fold ULN
Bridging necrosis or
multiacinar
necrosis on histological
examination
Incapacitating symptoms
Adapted from: http://www.aasld.org/practiceguidelines/Documents/AIH2010.pdf
Relative
Symptoms (fatigue, arthralgia,
jaundice)
Serum AST and/or c globulin
less than absolute criteria
Interface hepatitis
Osteopenia, emotional
instability, hypertension,
diabetes,
or cytopenia (white blood cell
counts 2.5 109/L
or platelet counts 50 109/L)
None
Asymptomatic with normal or near
normal serum AST and c globulin
levels
Inactive cirrhosis or mild portal
inflammation (portal hepatitis)
Severe cytopenia (white blood cell
counts <2.5 109/L or platelet
counts <50 109/L) or known
complete deficiency of TPMT
activity
precludes treatment with
azathioprine
Vertebral compression, psychosis,
brittle diabetes, uncontrolled
hypertension, known intolerances
to prednisone or azathioprine
 Clinical Outcomes
Goal is sustained remission free of medication
Treatment failure occurs in ~9 %
Early recognition allows for referral for transplant
Protracted therapy with clinical response but
not remission are maintained on lowest
possible dose of prednisone and steroid
sparing agent
Drug toxicity warrants discontinuation of
offending medication and implementation of
alternative medication
 Disposition
Referred for liver transplant
Started on high dose prednisone (40 mg or
more)
Added steroid sparing regimen as steroids are
tapered
Edema treated with furosemide and
spironolactone
Fertility and cirrhosis issues addressed
 Mr. Ho
56 year old Chinese male with known HBV
Saw hepatologist years ago but did not return
Never treated because of low viremia
Recently saw urologist who obtained US for
renal eval
Told there was a mass in his liver
 The Crime Scene
118/76, pulse 82, weight 134, height 55
Anicteric, no spider angioma or palmer
erythema, no HSM, no ascites, no LEE
 The Evidence
AST 34, ALT 35, AP 78, t bili 0.8, albumin 3.4
WBC 4.5, HGB 13.4, PLT 187,000
HBcAg +, HBsAg +, HBV DNA 21,000 IU/ml
INR 1.0
AFP 590
MRI 2.5 cm mass with wash out in right lobe
suggestive of primary HCC
Liver biopsy stage 3 fibrosis
 Confronting the Evidence
Asian male over age 40
Benign physical exam and well compensated
synthetic hepatic function
Probable life long infection
Low level of HBV viremia
Mass on US and elevated AFP
 Chronic HBV
350M persons affected worldwide, 1.25M in US
Rising in US due to emigration patterns
Vaccination of infants & children has decreased risk
Children with HBsAg+ should not be isolated
Increases risk of HCC, cirrhosis and
decompensation
Carriers should be counseled regarding
prevention of transmission
Vaccinate all household & sexual contacts
 Isolated HBcAb +
Chronic HBV infection with HBsAg levels below
the limit of detection but low levels of viremia
(think HIV)
Marker of recovery from past infection where
HBsAb decreased to undetectable levels
consider vaccination
False positive vaccinate patient
Window phase of acute infection (test HBc
IgM)
 Asian v. African Acquisition
Asian African
High or intermediate High or intermediate
prevalence rates prevalence rates
High risk of HCC in males High risk of HCC in males
over 40 and females over 50 and females over age 20
Higher incidence of HIV co-
infection
 Hepatitis B Vaccination
Vaccinate all at risk: sexual & household
contacts, newborns of HBsAg+ mothers,
health care workers & dialysis patients
Evaluate for immunity in at 9 to 15 months of
age of infants of carrier mothers, 1 2 months
after vaccination in other persons & annually
for dialysis patients
 Disposition
Referred to transplant center
Started on antiviral therapy to reduce viral
burden due to evidence of fibrosis on biopsy
Evaluated for segmental resection
Underwent radiofrequency ablation (RFA) and
listed for transplant
 Mr. Green
36 y/o male presents for an annual physical
C/O fatigue, RUQ pressure, inability to obtain
erection
Married, works in IT, no exercise, 3 children,
non-smoker, drinks on occasion
FH: Father deceased MI age 36, Mother alive
age 70 with CHF, pGF deceased age 39 MI,
pAunt with DM, brother alive age 33 HCV
 The Crime Scene
BP 145/90, pulse 76, weight 205, height 510
Tan appearing, anicteric, no spider angioma or
palmer erythema, liver 1 cm below RCM, no
spleen, masses or ascites, no LEE
 The Evidence
AST 35, ALT 39, AP 75, t bili 0.9, albumin 4.5
WBC 5.6, HGB 17.9, platelets 245,000
HCV Ab -, HBsAg -, HBsAb +
Iron 215, TIBC 235, % sat 93, ferritin 1975
 Confronting the Evidence
Well appearing male with complaints of
fatigue, RUQ pressure and ED
Elevated hemoglobin in non-smoker
Elevated % saturation and ferritin
FH suggestive of 1o relative with iron overload
Immune to hepatitis B, no exposure to HCV
 Hereditary Hemochromatosis
Under diagnosed but most common genetic
disorder affecting Caucasians (1:20-250)
Predisposition to inappropriate absorption of
dietary iron
Can lead to bronze DM, heart disease and
cirrhosis (with liver failure & HCC)
Defect substitution of tyrosine to cysteine at
282 position (C282Y) 80-85% of cases
Other substitutions at H63D & S65C
 HH Screening
Once a proband is identified, all 1o relatives
should be screened
Genotype (HFE) and phenotype (iron and
ferritin studies) should be performed
For children of HH patients, testing of the
other parent can be performed
If the other parent is unaffected, the child is an
obligate HH carrier and will not be affected
Liver biopsy to identify advanced fibrosis only
 HH Treatment
Phlebotomy until ferritin 50 100 g/L
Monitor every 10 12 phlebotomies
Each unit of blood contains 200-250 gm iron
Phlebotomize 1 2 times per week as tolerated
Can take up to 3 years to achieve desired ferritin
level
Avoid iron deficiency
Assess for need for maintenance phlebotomies
 Disposition
Seen by hepatologist
HFE homozygote for C282Y gene
Wife negative for mutation
Children will be heterozygote and will need
genetic counseling when appropriate
Liver biopsy stage 2 fibrosis, +4 iron
Begins weekly phlebotomy
Improvement in fatigue, RUQ pressure, & ED
 PCP Key Points
Obtain a good history
Look for physical clues
Dont brush off minor abnormalities in LFTs
Dig a little deeper
Refer when in doubt
Thank you and enjoy the rest of
the conference!