Sorting out the Diagnostics Ed Marino, PA-C Porter Adventist Hospital Liver Transplant Services Denver, CO

Sorting out the DiagnosticsSorting out the Diagnostics

Ed Marino, PA-CEd Marino, PA-CPorter Adventist Hospital Porter Adventist Hospital Liver Transplant ServicesLiver Transplant Services

Denver, CODenver, CO

AcknowledgementsAcknowledgements

Thanks to the organizers for my invitationThanks to the organizers for my invitation

Especially Corinna Dan, RN, MPHEspecially Corinna Dan, RN, MPH

Staff at Hepatitis Foundation InternationalStaff at Hepatitis Foundation International

Staff at Porter Hospital Liver Transplant Staff at Porter Hospital Liver Transplant Service for allowing me time away for thisService for allowing me time away for this

Educational ObjectivesEducational Objectives

Review the most common liver lab tests Review the most common liver lab tests

Determine true liver synthetic functionDetermine true liver synthetic function

Review viral hepatitis lab valuesReview viral hepatitis lab values

Discuss follow up for above labsDiscuss follow up for above labs

Hepatic PhysiologyHepatic Physiology

Liver: Liver:

Largest solid organ in the bodyLargest solid organ in the body

Performs over 500 chemical processesPerforms over 500 chemical processes

Produces over 160 different proteinsProduces over 160 different proteins

Makes clotting factors for the bloodMakes clotting factors for the blood

Stores & releases sugar as glycogenStores & releases sugar as glycogen

Metabolizes, detoxifies, synthesizesMetabolizes, detoxifies, synthesizes

The Anatomy of the LiverThe Anatomy of the Liver

CTCT

Liver HistologyLiver Histology

Defining TermsDefining Terms

Hepatitis: refers to any swelling, Hepatitis: refers to any swelling, inflammation, or irritation of the liverinflammation, or irritation of the liver

Over 100 causes including:Over 100 causes including:– Viruses, alcohol, enzyme deficienciesViruses, alcohol, enzyme deficiencies– Iron or copper overload, microvesicular fatIron or copper overload, microvesicular fat– Genetic disorders, licit & illicit drugs, toxinsGenetic disorders, licit & illicit drugs, toxins– Hypotension (shock liver / reperfusion)Hypotension (shock liver / reperfusion)


Inflammation that lasts long enough will Inflammation that lasts long enough will create fibrosiscreate fibrosis

Extreme fibrosis is called cirrhosisExtreme fibrosis is called cirrhosis

Cirrhosis can be either compensated or Cirrhosis can be either compensated or decompensateddecompensated

Compensated cirrhosis can be subtleCompensated cirrhosis can be subtle

Decompensated cirrhosis is more obvious Decompensated cirrhosis is more obvious

Normal Liver Normal Liver

Cirrhotic Liver Cirrhotic Liver


Normal Lab Values: 95% of normal, Normal Lab Values: 95% of normal, asymptomatic patients have numbers in asymptomatic patients have numbers in this range on a “bell shaped curve”this range on a “bell shaped curve”

Abnormal Labs: By definition, 2.5% of Abnormal Labs: By definition, 2.5% of normal patients have lab values either normal patients have lab values either above or below the “normal” range above or below the “normal” range

Liver “Function” TestsLiver “Function” Tests

ALT: alanine aminotransferase (SGPT)ALT: alanine aminotransferase (SGPT)

AST: aspartate aminotransferase (SGOT)AST: aspartate aminotransferase (SGOT)

Alkaline Phosphatase & BilirubinAlkaline Phosphatase & Bilirubin

Known as LFT’s (but they’re really not)Known as LFT’s (but they’re really not)

Liver Synthetic FunctionLiver Synthetic Function

Total Protein and serum albuminTotal Protein and serum albumin

Total BilirubinTotal Bilirubin

Prothrombin Time (PT / INR)Prothrombin Time (PT / INR)

These are “true” tests of liver functionThese are “true” tests of liver function

Traditional LFT’sTraditional LFT’s

ALT: ALT:

Found primarily in hepatocytesFound primarily in hepatocytes

Released when cells are hurt or destroyedReleased when cells are hurt or destroyed

Normal levels depend on the reference Normal levels depend on the reference range which actually differs lab to labrange which actually differs lab to lab

Considered normal between 5-40 U/LConsidered normal between 5-40 U/L

Probably should be half of this (5-20?)Probably should be half of this (5-20?)


AST: AST:

Found in many sources, including liver, Found in many sources, including liver, heart, muscle, intestine, pancreasheart, muscle, intestine, pancreas

Not very specific for liver diseaseNot very specific for liver disease

Often follows ALT to a degreeOften follows ALT to a degree

Elevated 2 or 3:1 (vs. ALT) in alcoholicsElevated 2 or 3:1 (vs. ALT) in alcoholics

Normal range: 8-20 U/LNormal range: 8-20 U/L


Alkaline Phosphatase: Alkaline Phosphatase:

Found in liver (especially biliary tract), Found in liver (especially biliary tract), bones, intestines, & placentabones, intestines, & placenta

““Fractionated” or “isoenzymes” to sourceFractionated” or “isoenzymes” to source

Liver AP rises with obstruction or Liver AP rises with obstruction or infiltrative diseases (i.e., stones or tumors)infiltrative diseases (i.e., stones or tumors)

Normal range: 20-70 U/LNormal range: 20-70 U/L


Bilirubin: two primary sourcesBilirubin: two primary sources

Indirect (unconjugated): old red cells, Indirect (unconjugated): old red cells, removed by the spleen, sent to the liverremoved by the spleen, sent to the liver

Liver “adds” glucuronic acid, making these Liver “adds” glucuronic acid, making these cells water soluble for excretion; now cells water soluble for excretion; now called direct (or conjugated)called direct (or conjugated)Normal range: less than 0.8 mg/dLNormal range: less than 0.8 mg/dL


Bilirubin: Indirect and directBilirubin: Indirect and direct

Direct (conjugated): Total bilirubin includes Direct (conjugated): Total bilirubin includes both direct and indirect typesboth direct and indirect types

Excreted in the bile, down the common Excreted in the bile, down the common bile duct, into the small intestinebile duct, into the small intestine

Normal range: 0.3 – 1.0 mg/ dLNormal range: 0.3 – 1.0 mg/ dL

Patterns of AbnormalPatterns of Abnormal

Elevations in ALT & AST only: suggests Elevations in ALT & AST only: suggests cellular injurycellular injury

Elevations in Alk Phos & Bilirubin: Elevations in Alk Phos & Bilirubin: suggests cholestasis or obstructionsuggests cholestasis or obstruction

Mixed pattern: ALT, AST, AP & Bili: Mixed pattern: ALT, AST, AP & Bili: probably the most common scenarioprobably the most common scenario

Patterns of AbnormalPatterns of Abnormal

Consider degree of elevation:Consider degree of elevation:

Very high ALT and AST usually only come Very high ALT and AST usually only come from a couple of sources:from a couple of sources:

Acute viral hepatitis (A,B,C, HSV)Acute viral hepatitis (A,B,C, HSV)

Acetominophen toxicity / overdoseAcetominophen toxicity / overdose

““Shock Liver”; cardiac or surgical event? Shock Liver”; cardiac or surgical event?

Most other items don’t cause huge levelsMost other items don’t cause huge levels

Viral HepatitidesViral Hepatitides

Hepatitis A, B, C, D, E, GHepatitis A, B, C, D, E, G

Cytomeglovirus (CMV)Cytomeglovirus (CMV)

Herpes Virus (HSV)Herpes Virus (HSV)

West Nile Virus (WNV)West Nile Virus (WNV)


Hepatitis A (HAV): Hepatitis A (HAV):

Food, water borne; heat labileFood, water borne; heat labile

Fecal - oral contamination; contagiousFecal - oral contamination; contagious

Usually self limited, lasting days to weeksUsually self limited, lasting days to weeks

99% spontaneous recovery, no treatment99% spontaneous recovery, no treatment

Tests: HAV IgM antibody = acute infectionTests: HAV IgM antibody = acute infection

HAV total antibody (IgM & IgG) = exposureHAV total antibody (IgM & IgG) = exposure

only, could be post infection or vaccinationonly, could be post infection or vaccination


Hepatitis B (HBV): Hepatitis B (HBV):

Blood, semen, saliva, vaginal secretionsBlood, semen, saliva, vaginal secretions

Highly contagious; sexually transmittedHighly contagious; sexually transmitted

90-95% self limited over 6 months90-95% self limited over 6 months

Chronic infection: >6 monthsChronic infection: >6 months

DNA virus: incorporates into host with DNA virus: incorporates into host with chronic infectionchronic infection


HBV Lab Tests:HBV Lab Tests:

HBV s Ag: surface antigen; + infectionHBV s Ag: surface antigen; + infection

HBV s Ab: surface antibody; - infectionHBV s Ab: surface antibody; - infection

HBV c Ab: core antibody IgM, IgG; only HBV c Ab: core antibody IgM, IgG; only + with infection, + with infection, notnot vaccination vaccination

HBV e Ag: envelope antigen; if + actively HBV e Ag: envelope antigen; if + actively replicating virusreplicating virus

HBV DNA: actual viral load in bloodHBV DNA: actual viral load in blood


Hepatitis C (HCV):Hepatitis C (HCV):

Blood borne, not in food or water; not Blood borne, not in food or water; not highly sexually transmitted*highly sexually transmitted*

Not highly contagiousNot highly contagious

20% self clearing; 80% chronicity 20% self clearing; 80% chronicity

RNA virus: does RNA virus: does notnot incorporate into host incorporate into host

Can cause HCC; #1 cause of transplantCan cause HCC; #1 cause of transplant


HCV Ab: + means past exposure; can take HCV Ab: + means past exposure; can take 3-6 months to form; not found if acute3-6 months to form; not found if acuteRIBA / ELISA: used to confirm Ab; + rules RIBA / ELISA: used to confirm Ab; + rules out false positivesout false positivesHCV PCR RNA: confirms actual viral HCV PCR RNA: confirms actual viral presence in blood; can be +/- or a viral presence in blood; can be +/- or a viral count (qualitative vs. quantitative)count (qualitative vs. quantitative)HCV Genotype: there are at least six (6) HCV Genotype: there are at least six (6) different (geno)types of HCV virusdifferent (geno)types of HCV virus


HCV Genotypes: different mutations of HCV Genotypes: different mutations of same virus (different branches, same tree)same virus (different branches, same tree)Can vary by global geographyCan vary by global geographyNotNot predicative of damage or symptoms predicative of damage or symptomsCanCan predict response to treatment predict response to treatmentCanCan be used to determine who is the best be used to determine who is the best treatment candidatetreatment candidateG1 & 4: most stubborn; G2 & 3: most G1 & 4: most stubborn; G2 & 3: most responsive; G5 & 6: most rareresponsive; G5 & 6: most rare

Evaluation StrategyEvaluation Strategy

Hepatocellular Injury:Hepatocellular Injury:

Liver biopsy remains the “Gold Standard” Liver biopsy remains the “Gold Standard” for diagnosisfor diagnosis

Biopsy is second only to a good historyBiopsy is second only to a good history

If a biopsy is obtained, you’ll need a very If a biopsy is obtained, you’ll need a very experienced pathologist to read itexperienced pathologist to read it

Consider sending it out if your local Consider sending it out if your local expertise is suspectexpertise is suspect


Advanced Imaging: Advanced Imaging: If RUQ US is questionable, and you’re If RUQ US is questionable, and you’re looking at a mixed picture: looking at a mixed picture: Consider an MRCP: non-invasive, Consider an MRCP: non-invasive, sensitive for ductal dilation (CBD, sensitive for ductal dilation (CBD, pancreatic ducts). Diagnostic, but non-pancreatic ducts). Diagnostic, but non-therapeutic. therapeutic. ERCP: Therapeutic, risk of pancreatitis, ERCP: Therapeutic, risk of pancreatitis, not available everywherenot available everywhere

Spider AngiomataSpider Angiomata

Spider NeviSpider Nevi

Nail ClubbingNail Clubbing

Dupuytren's Contracture

AscitesAscites

Jaundice or Scleral IcterusJaundice or Scleral Icterus


Clinical Pearls:Clinical Pearls:

Acute hepatitis panels Acute hepatitis panels nevernever consider acute consider acute HCV. If you have a IVDA pt, consider an HCV HCV. If you have a IVDA pt, consider an HCV PCR for acute hepatitis C. HIV?PCR for acute hepatitis C. HIV?

Consider celiac sprue for abnormal LFT’s, Consider celiac sprue for abnormal LFT’s, especially if you get a vague history of especially if you get a vague history of dyspepsia. Order TTG (tissue transglutaminase dyspepsia. Order TTG (tissue transglutaminase antibodies) with AGA (anti gliadin antibodies). antibodies) with AGA (anti gliadin antibodies).

SummarySummary

Liver tests are numerous and somewhat Liver tests are numerous and somewhat confusingconfusing

Not all liver disease is associated with Not all liver disease is associated with abnormal test resultsabnormal test results

Some of the worst liver disease has Some of the worst liver disease has relatively normal appearing LFT’s and can relatively normal appearing LFT’s and can only be noticed with a look at synthetic only be noticed with a look at synthetic functionsfunctions

SummarySummary

AllAll abnormal liver tests should be abnormal liver tests should be investigatedinvestigated

Referral to an expert is absolutely neededReferral to an expert is absolutely needed

Liver biopsy is the “Gold Standard” for Liver biopsy is the “Gold Standard” for diagnosisdiagnosis

Family histories of liver disease should be Family histories of liver disease should be noted: “.…my grandmother died of noted: “.…my grandmother died of cirrhosis, but she never drank….”cirrhosis, but she never drank….”

Thank You! Thank You!

My contact information: My contact information:

Ed Marino, PA-CEd Marino, PA-C

Porter Hospital Liver Transplant ServicePorter Hospital Liver Transplant Service

2535 S. Downing St., Suite #3802535 S. Downing St., Suite #380

Denver, CO 80210Denver, CO 80210

[email protected]@centura.org

Wk. 303.778.5797 Fax 303.778.5205Wk. 303.778.5797 Fax 303.778.5205

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Sorting out the Diagnostics Ed Marino, PA-C Porter Adventist Hospital Liver Transplant Services Denver, CO