Download - St. Charles Advanced Illness Management · 2019-10-10 · • Persistently elevated LFTs for several years • Felt to be due to fatty infiltration seen on Ultrasound by PCP as patient

Terrance M. James, NP-CSt. Charles Advanced Illness Management

Elevated Liver Function Tests:A Case Based Approach

• Identify patterns of abnormal liver function tests

• Identify appropriate choices of liver related laboratory tests

• Identify appropriate choices for liver imaging studies

• Identify the elements that make the diagnosis of particular liver diseases

Objectives

• Have they been confirmed more than once over a 1-2 month window?

When are liver chemistries considered abnormal?

• Is the pattern consistent, changing, or evolving?


• What has changed in their history? Medications? Substances? Supplements?


ALT >30 IU/L males or, ALT >19 IU/L females or,

ALP >120 IU/L

Repeat & confirm in 1-2 mo

If resolved, repeat in 3-12mo

if alcohol, illicit drug use, medications orsupplements (inc. herbal) suspected:

adjust and repeat in 3mo

Total bili >5 and,abnl ALT +/- abnl ALP

Urgent u/sHbsAg, HBcAb IGM

HAV Ab IGM

Consider GI referral

Isolated total bilirubin

Fractionate bilirubin

>15% direct

Dubin-Johnson orRotors syndrome

<15% direct

Evaluate for hemolysis

neg

Gilbert’s syndromeHepatocellular1 Cholestatic2 Isolated ALP elevation3

U/S

Ducts normal Ducts dilated

MRCP, ERCP+/- EUS

AMAneg

ERCP &liver biopsy

pos

Liver biopsy

Fractionate or√GGT or 5’ nucleotidase

Liver origin or,GGT pos, 5’ neg

Bone origin or,GGT neg, 5’ pos

Bone evalu/s, √AMA

Review recent meds

u/s: ducts normal,parenchymal dz&/or AMA pos

Liver biopsy

Dilated ductsAMA neg +/- hx IBD

ERCP

HbsAg, antiHCV, serum Fe,TIBC, ferritin; u/s

pos

Further evalHBV: HBeAg, DNA level

HCV: PCR, genotype

Consider liver biopsy

Consider therapy

neg

ANA, SMA, ceruloplasmin,Α1-antitrypsin level,Consider celiac eval

Serologies neg;u/s pos fatty liver

treat

Incidental finding ofAbnormal LFTs

If acute hepatitissuspected

= refer to GI

1. Cholestatic

2. Hepatic

Patterns of abnormal liver function tests

• Alkaline phosphatase higher than AST/ALT levels• Alkaline phosphatase higher with near normal

AST/ALT levels – sometimes referred to as infiltrative pattern

• Bone, first trimester placenta, kidneys and intestines can also lead to elevations in Alkaline phosphatase

• Adding on a GGT can help determine if this is a liver process in the setting of Alkaline phosphatase > AST/ALT

1. Cholestatic

• Alkaline phosphatase higher than AST/ALT levels

Cholestatic



Cholestatic




• Adding on a GGT can help determine if this is a liver process in the setting of Alkaline phosphatase > AST/ALT

1. Cholestatic

AST and or ALT Alkaline phosphatase

Hepatic/Hepatocellular

Higher Than

Skeletal muscleCardiac muscles Red blood cells Kidneys


Elevations in AST/ALTCan All Lead To

When AST is 2x greater than ALT: Add a GGT to help determine if it’s an alcoholic injury


• Platelets – helpful to determine the extent and length of disease, low platelets think low function

• Bilirubin – high bilirubin reflects poor liver function and high amount of liver injury

• Albumin – low albumin reflects changes in their nutritional status that could be related to their liver disease

• INR – high INR think liver damage and poor function

Other Labs

• 60 year old white male, originally from the New York area, resettled in Portland 20+ years ago

• Persistently elevated LFTs for several years

• Felt to be due to fatty infiltration seen on Ultrasound by PCP as patient has diabetes, high cholesterol and high blood pressure; he also has RLS, colon polyps, HSV2, GERD, ED, and Achilles Tendonitis

• He is a gay male, happily married to same partner for 20 + years

• Reports distant IV and intranasal drug use “It was the 70’s”

• Family history of metabolic disease, alcoholic liver disease and “I think someone had cirrhosis”

• Has reports of frequent fatigue, “since I got diagnosed with Diabetes,” about 15 years ago

Our First Case….Meet Hal

Mrs. Nguyen• 35 yo Vietnamese Female, newly pregnant at 13 weeks, routine screening shows

her Hep B positive – Surface Ag positive• E antigen positive, DNA 70 million, AST 22, ALT 18, ALK Phos 40, Bili 0.8• Mother and 2 brothers with Hep B• Daughter has been vaccinated, Spouse unknown vaccine or disease status• Follow-up at 28 weeks shows DNA of 54 million

Wesley• 38 year old married accountant • Has noted sudden onset of jaundice, icterus,

abdominal swelling and lower extremity swelling about 1 week prior to presentation; wife wanted him to come in early for this but he refused

• Felt weak last night and presented to PCP• Noted to be hypotensive 88/58, Pulse 122• Not making urine, can barely get from chair to the

bed• Massive ascites on exam, 3+ pitting edema, he has

telangiectasias and spider angiomata

William• 29 yo mixed race male (white and Chinese)• BMI of 53• Has hyperlipidemia and hypertension• Drinks 2-3 beers most nights, more on the weekends• Lab at PCPs office: alkaline phosphatase 128, , AST

70, AST 56, T Bili 1.1, A1c 5.8, Triglycerides 400, GFR >60

• Liver US shows increased echogenicity• Quit drinking for 2 months• Follow-up labs: ALT 59, ALT 50T Bili 1.0, Ferritin 865

– referred to GI

Tina• 24 year old mixed race female• Used heroin and meth from age 16 to 23• Clean and sober for 5 months• Tested positive for Hep C ab in rehab• Presents to clinic with her mother for discussion of

treatment• Recent flu like illness and massive fatigue that are

now gone • No recent LFTs, never had a HCV Quant PCR

Ernest• 55 yo African American male• Uses heroin intranasal now but prior IV use• Hep C for at least 29 years• Hx of Hep B and jaundice but told that he cleared it• Prior Interferon/Ribavirin non-responder• Told at that time he was cirrhotic• Has not seen primary care in 10 years, recently re-established

and now wants “Harvoni,” like on TV per referral• Has RUQ pain, changes in appetite and weight loss

• 29 yo mixed race male (Caucasian and Chinese)• BMI of 53• Has hyperlipidemia and hypertension• Drinks 2-3 beers most nights, more on the weekends• Lab at PCPs office: alkaline phosphatase 128, , AST



– referred to GI

Chet

• Substance History – we know he used IV and intranasal drugs so did you get hepatitis?

• Viral Hepatitis – CDC recommendations currently anyone born between 1945 and 1965 ie. > 50 needs Hep C checked

• Autoimmune History – patient and family – if patient or family member has an AI disease, chances are higher for other autoimmune disease

• Bleeding – signs of low platelets and high INRs

What questions should we ask?

• 60 year old white male, originally from the New York area, resettled in Portland 20+ years ago

• Persistently elevated LFTs for several years

• Felt to be due to fatty infiltration seen on Ultrasound by PCP as patient has diabetes, high cholesterol and high blood pressure; he also has RLS, colon polyps, HSV2, GERD, ED, and Achilles Tendonitis

• He is a gay male, happily married to same partner for 20 + years

• Reports distant IV and intranasal drug use “It was the 70’s”

• Family history of metabolic disease, alcoholic liver disease and “I think someone had cirrhosis”

• Has reports of frequent fatigue, “since I got diagnosed with Diabetes,” about 15 years ago

Our First Case….Meet Hal

• Meformin XL 500 mg, Atorvastatin 10 mg, Lisinopril 10 mg, Requip 0.25 mg, Cialis 20 mg, and ASA 81 mg

• BP 118/74, P 81, BMI 26• Alkaline Phosphatase 54• ALT 87 (79 one year ago)• AST 52 (48 one year ago)• Bilirubin total 1.1• Albumin 3.8• Total Protein 6.6• A1c 6.3• LDL 88, Triglycerides 125

Our Case….Meet Hal

• Had Hep B he thinks in 1973, and in 1978 had Hep A, no subsequent checks or testing

• He and his partner love Italy/Italian food and wine; drink at least one glass of wine a night

• Thinks he has had high liver function tests for a long time

• Smokes some pot and eats edibles to help with sleep and RLS

• No autoimmune disease but thinks a cousin had an issue with iron

• Never had any acute bleeding events

Now that you mention it….

• Hep B surface antigen negative, core IgM negative (surface antibody and core IgG positive = proof of old infection)

• Hep C antibody negative• GGT, serum ethanol, FibroSure negative• ANA, ASMA negative• Alpha-1 antitrypsin negative• INR 1.0• WBC 7.7, RBC 4.08, Hgb 13.2, Hct 39.3, Platelets 268

Results

• Alcohol related injury – GGT, serum ethanol, ETG, serum fibrosis testing – FibroSure NASH

• Iron Studies – iron, total binding capacity, and ferritin

• Autoimmune markers – ANA, Anti-Smooth Muscle Antibody (if it had been a cholestatic picture Anti-Mitochondrial Antibody)

• Genetic disease – Hemachromatosis (Iron studies will lead you to this) and Alpha-1 antitrypsin

• Check an INR

Where to go from here?

• 38 year old married accountant • Has noted sudden onset of jaundice, icterus,

abdominal swelling and lower extremity swelling about 1 week prior to presentation; wife wanted him to come in early for this but he refused

• Felt weak last night and presented to PCP• Noted to be hypotensive 88/58, Pulse 122• Not making urine, can barely get from chair to the

bed• Massive ascites on exam, 3+ pitting edema, he has

telangiectasias and spider angiomata

Wesley

Wesley

• Noted to have the following labs: alkaline phosphatase 338, AST 689, ALT 345, T bili 8, BUN 40, Creatinine 4, GFR <15, INR of 3.2, Serum Albumin 1.8

• MELD of 40• Abdominal US shows massive ascites, abdominal

varices, and a recannulated umbilical vein• Diagnostic paracentesis shows WBCs 300, culture

positive for Strep pneumoniae, started on Ceftriaxone• Rapidly reaccumulated ascites, worsening renal

function, required dialysis, thoracentesis, and is still in the hospital after 1 month

Wesley

Mrs. Nguyen• 35 yo Vietnamese Female, newly pregnant at 13 weeks, routine screening

shows her Hep B positive – Surface Ag positive• E antigen positive, DNA 70 million, AST 22, ALT 18, ALK Phos 40, Bili 0.8• Mother and 2 brothers with Hep B• Daughter has been vaccinated, Spouse unknown vaccine or disease

status• Follow-up at 28 weeks shows DNA of 54 million• Treat for last trimester with Tenofovir – safe in 3rd trimester• Stop treatment at birth • Check labs through first 6 months after birth – if her chems stay normal

no need for treatment, if they do not improve restart treatment and stop breastfeeding

• She did not require further treatment – continuing labs every 6 months with her PCP

• Viral Hepatitis Testing – Hep B surface antigen and core IgM– Hep C antibody with reflex to

quantitative– No need for Hep A testing in this

setting of suspected chronic liver disease, ie. Persistently elevated liver tests

When you need to look for Hepatitis….

High ModerateLow/Not

Detectable

blood semen urineserum vaginal fluid feces

wound exudates saliva sweattears

breastmilk

Concentration of Hepatitis B Virus in Various Body Fluids

Sexual - sex workers and homosexuals areparticular at risk.

Parenteral - IVDA, Health Workers are atincreased risk.

Perinatal - Mothers who are HBeAg positive aremuch more likely to transmit to their offspringthan those who are not. Perinatal transmission isthe main means of transmission in highprevalence populations.

Hepatitis B Virus Modes of Transmission

Hepatitis B treatments• Entecavir 0.5 mg and 1.0 mg daily – No renal issues, no problems with

Phosphorous levels

• Tenofovir Disoproxil 300 mg – low rates of resistance, potential for renal issues and bone loss, can cause hypophosphatemia

• Tenofovir Alafenamide 25 mg – Pro-drug of Tenofovir, not associated with renal or bone loss issues, no issues with phosphorous

• Pegylated Inteferon – only potentially curative treatment, but risks or therapy outweigh the benefits

Hepatitis B

Elevated serum ALTMales >30 IU/L; females >19 IU/L

Screening ‘at-risk’patient

HBsAg pos

If not previously drawn:Anti- HAV(total)

Anti- HCVHBeAg/ HBeAb

Vaccinate againsthepatitis A See hepatitis C algorithm

Consideration oftherapy and/or biopsy1

Treatment completed2

Treatment notInitiated

Repeat HBV DNAq6mo

TreatmentInitiated

Repeat HBV DNAq4mo

HBV DNA (quant)

Begin age-appropriate hepatoma screeningRefer to hepatology

neg

pos

Hepatitis D – you can’t have D if you don’t have B!

• The virus represented by Hepatitis D needs the presence of Hepatitis B to survive in the human body

• When you check for Hepatitis B you should check for D

• Makes it less likely for Hep B to become a chronic infection, but can occur

• Liver Ultrasound – great screening test for liver injury and disease

• CT and MRI – particularly helpful when looking for cancer

• Hepatitis B – all patients with Hep B should be getting appropriate age and race related screening for Hepatoma - #1 reason for healthcare related lawsuits in Asian patients –aasld.org/publications/practice-guidelines

Imaging

• We utilize RUQ ultrasound and AFP tumor markers for hepatoma screening

• Know your local resources – tumor boards at Portland Providence Medical Center and OHSU if you have concerns or questions about something you find on imaging

• Definitive testing for Hepatoma is a Triple Phase CT or MRI, also called a dynamic liver exam

• Not every hepatoma puts out AFP which is why it has fallen out of favor but many practitioners do still use it

Hepatoma Screening

• You need iron testing when looking at this for HH –you should ask

• They will comment on the amount of steatosis and fibrosis

• The pathologist will also comment on which stains were read and how they fit into the diagnostic picture

• Don’t be afraid to have the pathology be sent out for second opinion – Chris Corless, MD at OHSU is a good resource

Biopsy

Tina• 24 year old bi-racial female• Used heroin and meth from age 16 to 23• Clean and sober for 5 months• Tested positive for Hep C ab in rehab• Presents to clinic with her mother for discussion of

treatment• Recent flu like illness and massive fatigue that are

now gone • No recent LFTs, never had a HCV Quant PCR

Tina• AST 22, ALT 20, T Bili 0.7, Alk Phos 65• HCV Quant <15• Hep B S Ag non-reactive• Hep B S Ab <3.10• Hep B Core total Ab non-reactive• HIV non-reactive

Spontaneous Viral Clearance• Between 25-30 % of patients will spontaneously

clear Hepatitis C• Usually a younger co-hort• We often see this in young recently clean patients• Often have a robust immune response with “flu-like”

prodrome and very elevated transaminases that then fall to normal along with a negative viral quantitative PCR

How to screen

Hepatitis C online, Univ of Wash, Dr David Spach

Baby boomers(+ other high risk pops) Screen for HCV

positive

Assess forFibrosis

FibroMeter/Scan / +/-biopsy

vaccinations

SurveillanceFibroSure/Scan

PCPs / ID / NPs

GI or Hepatology

F0-2Compensated F3-4, F2+manifestations

Hep panel, CBC, PT/INRHCV quantitative PCRHCV genotypeAnti-HAV; HBsAg/AbFe/TIBC/ferritin

In the near future this will be you!

The most efficient approach to fibrosis assessmentis to combine direct biomarkers and vibration-controlledtransient liver elastography. (Boursier, 2012) A biopsy should be considered for any patient who has discordantresults between the 2 modalities that would affect clinicaldecision making –AALSD/IDSA Guidance

Although an ideal interval for assessment hasnot been established, annual evaluation isappropriate to discuss modifiable risk factorsand update testing for hepatic function andmarkers for disease progression. For all individualswith advanced fibrosis, liver cancer screeningdictates a minimum of every 6 months evaluation-AASLD/IDSA Guidance

Role of PCP

Ongoing cirrhosis care

Patient educationPrescribes drugSide effect managementDose adjustmentMonitors compliance

340bpharmacyDispenses drug

http://www.hcvguidelines.org/full-report/references#boursier2012

TransducerHigh-powered u/s pulse

generates “shear waves” the velocityof which are measured

3cm

Velocity (V-m/s) of the waves is affected by elasticity (E-kPa) and are related by the formula E = 3ρV2. The stiffer the tissue, higher elasticity, the faster thewaves travel.

Elastography

While in this view the tech (Joel) selects those areas where the lines run the most in parallel.Speed measurements are taken from there. The faster the waves move, the wider theSpaces between the lines.

Ernest• 55 yo African American male• Uses heroin intranasal now but prior IV use• Hep C for at least 29 years• Hx of Hep B and jaundice but told that he cleared it• Prior Interferon/Ribavirin non-responder• Told at that time he was cirrhotic• Has not seen primary care in 10 years, recently re-established

and now wants “Harvoni,” like on TV per referral• Has RUQ pain, changes in appetite and weight loss

Ernest• LFTs – AST 78, ALT 88, T Bili 2.1• INR 1.5; Platelets 88; Albumin 2.7; AFP 78• Genotype 3; HCV Qnt PCR 8 mill• US with Elastography shows nodular appearance

with F4 level fibrosis• CT Dynamic Liver showed 3 < 3 cm masses in L lobe,

Li-Rads 5 lesions = HCC

Hep C Case #2• Not eligible for transplantation due to active

substance abuse• Resection candidate if he could get sober for 3

months• Failed to respond to calls• Presented to Providence ED in end-stage liver

disease• Placed on comfort care and passed

Current Hepatitis C Treatments

• Genotypic• Harvoni +• Viekira (triple therapy) *• Sovaldi• Daklinza• Zepatier *• Simeprevir

• Pangenotypic• Epclusa• Mavyret * + #• Vosevi (triple therapy) #

*Can be used in renal disease regardless of GFR+ 8 weeks of treatment in non-cirrhotic patients# No Ribavirin required in cirrhotic patients

Choosing a Drug• Most choices are due to insurance coverage –

formulary drug• Prices are going down• We predict this will be a Primary Care role in the

next 12-36 months

• 29 yo mixed race male (Caucasian and Chinese)• BMI of 53• Has hyperlipidemia and hypertension• Drinks 2-3 beers most nights, more on the weekends• Lab at PCPs office: alkaline phosphatase 128, , AST



– referred to GI

Chet

Chet• Autoimmune panel negative, negative

ceruloplasmin, Hemochromatosis CY282 heterozygote

• NAFLD FibroMeter F3, elevated NASH score• Elastography F0/F1• Decision made to biopsy his liver• Biopsy shows moderate steatotosis, mild

steatohepatitis, grade 1, stage 1 level fibrosis• Decision made to refer patient to bariatic surgery

and nutritionist

Normal

Stage 1

Stage IV

Incidence:• Not well known – no prospective biopsy studies

• Recent meta analysis suggested– Asia 52/1000 person-years– West 28/1000 person years

Younossi ZM Hepatology 2016. 64:73

Prevalence:Global 25% NAFLD

1.5 – 6.5% NASH

Mid East/South America 30% Africa 13%

Younossi ZM Hepatology 2016. 64:73

Prevalence in ‘high risk’ pops:

AASLD Practice Guidance. Hepatology 2017

ObesityT2DMDyslipidemiaMetabolic SyndromePolycystic Ovary Syndrome

T2DM• 30-60% have NAFLD

• Can appear simultaneously

Dyslipidemia

50% NAFLD among lipid clinic patients

Assy, Dig Dis Sci 2000;45:1929

Leite. Liver Int 2009;29:113

Ong JP, Younossi ZM. Clin Liver Dis 2007;11:1-16

Predictors of “Bad” NASH:

Management:

Hannah WN, et al. Clin Liver Dis. 201. Vilar-Gomez, et al. Gastroenterology 2015; 149:367-378.

Treatment: % Weight Loss Associated with Histological Improvement

Life style- dietary change and exercise

Nonalcoholic Fatty Liver Disease: Epidemiology, Natural History, and Diagnostic Challenges

HepatologyVolume 64, Issue 3, pages 954-954, 2 AUG 2016 DOI: 10.1002/hep.28719http://onlinelibrary.wiley.com/doi/10.1002/hep.28719/full#hep28719-fig-0001

http://onlinelibrary.wiley.com/doi/10.1002/hep.v64.3/issuetoc

http://onlinelibrary.wiley.com/doi/10.1002/hep.28719/full#hep28719-fig-0001