Transcript Liver Functions and Abnormalities

Liver Functions and Abnormalities
ALT, AST, AP
Bilirubin - Direct and Indirect,
PT, INR, Albumin, GGT
Viral Hepatitis profile, ANA , SMA, AMA , Globulins ,
Ammonia, Ferritin, Transferrin saturation ,Iron profile ,
Ceruloplasmin, Alfa –Fetoprotein , Alpha 1 Antitrypsin
• Plain abdomen , U/S, CT, MRI,MRCP, ERCP
• Liver biopsy
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ALT, AST, Bilirubin, AP
Becoming “Routine “
Screening for Liver disease (not liver function)
Useful , non invasive
Assess severity
Predominant Hepatocellular and Cholestatic.
Follow up liver disease
Evaluate response to treatment .
May predict outcome
Drawbacks:
Lack sensitivity(Normal results in liver disease (NAFLD ,
HCC or Cirrhosis )
o Not specific for liver disease (elevated in heart or muscle
injury …)
o They don’t lead to a specific diagnosis… we need to repeat
them with a battery of other tests
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Abnormal Liver Function Tests !!
( ALT, AST & AP )
“ LFTs “Doesn’t measure Liver Fxn but “ screen” for liver disease
Normal results in Liver disease !!
Abnormal results in healthy liver !!
9 % Asymptomatic patients have mildly elevated AST or ALT
In ~ 30 % will be normal by just repeating it
The higher the BMI, weight and visceral obesity the more abnormal
In most cases an underlying serious liver disease is Unlikely
Patients with abnormal Transferase subjected to Liver biopsy :
(~ 84 % Steatosis , Steatohepatitis , ~ 6 % Fibrosis and Cirrhosis
and ~ 10 % normal liver histology )
• Currently in the US : Commonest causes : NAFLD , Alcoholic Liver
disease and Chronic Hepatitis C .
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Aminotransferases
Alanine and Aspartate Transaminase
• (ALT ) & (AST ) Intra Cellular Enzymes in the hepatocytes
Involved in amino acid metabolism .
• Released into circulation when the hepatocytes are injured
• ALT : Primarily found in the liver but in small amount in
skeletal muscles .
• AST : Not only found in the liver but also in the cardiac
muscle, skeletal muscle, kidneys, brain, pancreas, lungs…
• ALT & AST elevation is non specific , the exception is when
AST/ALT ratio is more than 2 suggesting alcoholic liver disease
…because pyridoxal-5'-phosphate ( the active form of pyridoxine =
Vit B6 ) is needed for ALT synthesis but is less essential for AST
synthesis , this is deficient in chronic alcoholics . This deficiency also
explains why in alcoholic patients , ALT & AST elevation are not that
high (< 300 IU/L)
Elevated Transaminases …
What next ?
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History:
Medications, OTC, Alcohol, Herbs
Duration and trend
Ask about IVDU, Blood transfusion, Tattoo’s , Travel Hx and alcohol
F Hx: Hemochromatosis, PBC, Wilson’s and Alpha One Anti Trypsin
Symptoms : ( Jaundice , fever, weight loss, pruritus, arthralgia, rash,
abdominal / RUQ pain ) Steatorrhea, Loose fatty stools with cholestasis
Physical exam :
RUQ Tenderness and Murphy’s sign. Hepatomegaly, Splenomegaly
Jaundice, muscle wasting , spider angioma, palmer erythema,
gynecomastia, Ascites , pleural effusion
Duputryn’s contracture, parotid swelling,
Lab: ? Hepatocellular or Cholestatic ??
Hepatocellular or Cholestatic
• Predominant ALT & AST:
• ALT & AST are released into circulation when hepatocytes are
injured …If predominant …Think Hepatocellular …
• Hepatitis Profile, ANA , SMA, SPEP , AMA , Iron Transferrin
saturation and Serum Ferritin...
• U/S for Fatty Liver …
• Predominant AP :
• AP is released into the blood stream when there is obstruction to
bile flow …Check GGT = Liver source  Cholestatic
“ interference with bile flow ”
Extra Hepatic ? or Intra Hepatic ? ?
Hepatocellular : Predominant ALT & AST
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1. NAFLD : Steatosis ( NAFL ) and Steatohepatitis (NASH) : -> Imaging
2. Alcoholic Liver Disease suggested by AST/ALT ratio > 2 or > 3 ,
Elevated GGT in those patients also suggests alcohol abuse .
3. Chronic Hepatitis C and B ( ~ 85 % of acute HCV  Chronic Hepatitis )
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Hemochromatosis : Iron panel, Transferrin saturation -> Biopsy
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Medications: Including OTC & Tylenol (Statins ,NSAIDs, Abx , Anti Seizure, Anti
TB , HIV, MTX, AZA, Amiodarone , Methyldopa , Nitrofurantin, PTU Captopril … )
Herbs ….
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A I H : Young Females with “hepatitis” ANA, SMA, SPEP, Globulin Biopsy
Alpha One Anti Trypsin Deficiency : Young, Emphysema
PBC : Middle age Female with pruritis , Very high AP … AMA  Liver biopsy
Wilson’s : Young , Low Ceruloplasmin, Kayser Fleisher rings , 24 hour urinary
cupper
Cholestasis : Predominant AP
“ interference with bile flow
Check for Obstruction by U/S ( or CT)
• U/S : if shows Dilated Bile Ducts
= (Extra hepatic Cholestasis )  MRCP
( Choledocolithiasis “ most common “ , Malignant disease of the
pancreas, GB, CBD, or of the ampulla , Chronic pancreatitis causing
CBD stricter, PSC Primary Sclerosing Cholangitis (intra and extra
hepatic in 2/3 cases )… look for IBD ) … ERCP.
• U/S does NOT show bile duct obstruction
o (Intra Hepatic Cholestasis) ( PBC, PSC, Drug induced Cholestasis )
for PBC check AMA , if positive AMA  LIVER BIOPSY to confirm
o If negative U/S and negative AMA …check for PSC ( Primary
Sclerosing Cholangitis by MRCP (~ 1/3 intra hepatic )
o Drug induced Cholestasis: ( Phenothiazine's, Tricyclic's, Bactrim,
Ampicillin, Dicloxacillin, Augmentin, Erythromycins …Androgens ,
Estrogens ) usually this is reversible
• Alkaline Phosphatase Sources: (liver, bone, placenta and kidney)
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A P Fractionation  GGT ( γ - Glutamyl Transpeptidase) ~ liver specific
• High levels of AP > four fold the normal ~ 500 usually seen in
prolonged Cholestasis in most cases.
• Elevated In extra and intrahepatic obstruction , the extent does not
differentiate between either, does can not help identify etiology
(CBD stone or stricture, Ca, PSC , Drug-induced hepatitis , PBC )
• Modest increases in AP ~ Three times the normal ~ 350 are
nonspecific and may occur in any liver disorders (acute viral
hepatitis, chronic hepatitis, cirrhosis, infiltrative liver diseases and
CHF)
• Isolated AP elevation or disproportionate elevation of AP to AST,
ALT (Obstructed Bile duct 2 to Gall stones or tumor, Infiltrative
diseases e.g. Sarcoidosis, TB, Mets… )
• High GGT :In alcoholics even with normal Transaminases and
Bilirubin , The possible explanation is the induction of hepatic
microsomal GGT by alcohol , also alcohol may cause leakage of
GGT from hepatocytes.
• Albumin and PT reflects the Synthetic Capacity Of Liver
• Albumin: Synthesized by hepatocytes , has a Long half life ~
20 days, 4 % degraded daily , therefore …slow turnover
Albumin is not good indicator of acute or mild disease
• Normal Albumin = Acute process (Viral Hepatitis) Gall stone
Obstruction
• Low Albumin = Chronic process (Cirrhosis )
PT: measures factors II, V, VII, and X , Made almost
exclusively in the liver short half life , rapid turnover , good
indicator of liver synthetic function.
• Increased PT =
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* Vitamin K deficiency (prolonged jaundice or malabsorption ) or
* end stage liver failure  if does not correct with Parenteral Vit K
= Severe liver dysfunction .
Hematologists are trying “ Non invasive markers “ for Fibrosis
Fibro test and Fibro Sure :
Predicts Chronic Liver Inflammation or Fibrosis in NAFLD
( Alpha 2 Macroglobulin, Alpha 2 Globulin (Haptoglobin), Gamma
Globulin, Apo lipoprotein A1, Gamma Glutamyl Transferase and Bilirubin )
NAFLD Fibrosis Score Calculator :
Age, BMI, PLT, Hyperglycemia, Albumin, AST/ALT ratio
Hepascore
Predictor of Liver Fibrosis In Chronic Hepatitis C
(Bilirubin , GGT, Hyaluronic Acid, Alfa 2 Macroglobulin, Age & Gender )
“ NAFLD Fibrosis Score is a clinically useful tool for identifying NAFLD
patients with higher likelihood of having bridging fibrosis and/or cirrhosis.
“ (Strength – 1, Evidence - B)
Hyperbilirubinemia
Bilirubin  Unconjugated and conjugated
Isolated Unconjugated Hyperbilirubinemia
Other liver functions are normal
 Increased Production : Hemolysis:
( Increased Reticulocytes and Haptoglobin )
 Impaired Uptake: Meds …Rifampicin .
 Impaired conjugation : Gilbert's & the rare Criggler Najjar
Isolated Conjugated Hyperbilirubinemia
( Decrease execration into the bile duct or defective liver storage )
Rare Dubin Johnson and Rotor Syndrome
Hyperbilirubinemia
Unconjugated and conjugated
Balance between production, conjugation and excretion
In Liver Diseases ( both fractions are elevated )
Conjugated ( Direct) Hyperbilirubinemia
Hepatocellular and Cholestatic
( Liver Or Biliary Disease )
Unconjugated ( Indirect) Hyperbilirubinemia
Hemolytic Diseases
Bilirubin Metabolism
• RBC dies  Hemo globin …bound to Haptoglobin …Transported
to RES  (Globin, iron, and Heme )
• Heme oxidized to Biliverdin converted to Unconjugated Bilirubin
(Water insoluble ) tightly bound to albumin cannot be execrated 
transported to liver , conjugated by Glucoronyl Transferase to
Glucuronic acid (Conjugated Bilirubin is water soluble ) stored in
Gall Bladder eventually excreted into the duodenum and passes
into the large intestine, Bacteria converts it to Urobilinogen ,
oxidized to Urobilin and Stercobilin …which gives feces its
brownish color.
• 95% of the Conjugated Bilirubin reabsorbed from small intestine
(Enterohepatic Circulation) Re-secreted into the liver and into the
small intestine again
• Some of the Urobilinogen is reabsorbed and 95% of this reabsorbed
is re-secreted in the bile (part of Entero hepatic circulation )
• About 5% of the reabsorbed urobilinogen is excreted in urine
following further oxidation to Urobilin which gives urine its
characteristic yellow color.
• Urine Bilirubin : All Bilirubin in urine is conjugated( water soluble )
urine Bilirubin means (liver disease or blocked Bile ducts ) because
there is increased serum Bilirubin , some of this conjugated Bilirubin
will leak out of hepatocyte and show in urine and gives it’s dark
amber color
• The Unconjugated Bilirubin is water insoluble , bound to albumin ,
and not execrated in urine ( except in severe renal disease )
• Urine Urobilinogen : In hemolytic anemia -> excessive RBC‘s
broken down  increased Unconjugated Bilirubin (Not water
soluble) therefore no increase in Urine Bilirubin .
• Because there is no problem with the liver or Biliary tract , the
excess conjugated Bilirubin is excreted into bile -> metabolized to
urobilinogen … Reabsorbed  Increase in urine urobilinogen.
• Other causes of Urine Urobilinogen: ( liver diseases, hepatitis,
cirrhosis, Mets )
Non Hepatic Causes of Elevated AST or ALT
AST and ALT are also increased in Non-liver disease
• (Myositis, Muscle Trauma , Heavy exercise , M I , Myocarditis,
Pulmonary infarction, Thyroid disorders ,Celiac disease , Adrenal
insufficiency Dermatomyositis, Anorexia Nervosa , Seizure
disorder, Hyperthermia )
• If …of muscle disorder or muscle source  CPK , LDH and
Aldolase are increased …
• If …Thyroid check TSH
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Aminotransferase Elevation
Mild increases
(< 300 IU/L) Nonspecific …
NAFLD, Alcoholic liver disease , Cirrhosis, HCC, Cholestasis
Modest elevations
(300 to 500) Chronic liver disorders
(Alcoholic Hepatitis, Biliary Obstruction and Chronic Hepatitis )
Markedly high values > 500 IU/L = Acute Necrosis or injury
Acute Viral Hepatitis , Drug-induced , Ischemic Hepatitis
Acute setting of AIH , Gall stone obstruction
Aminotransferases can be normal in :
NAFLD , Cirrhosis , Chronic Hepatitis C , HCC &
Hemochromatosis…
Aminotransferases
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Acetaminophen & Toxins: Rises Rapidly to > 2000
Acute Viral Hepatitis : Rises Gradually to ~2000
A I H : Rises Gradually to ~ 1000
CBD stone / Obstruction : Rapidly rise ~ 1000
Alcoholism AST > ALT : Gradually ~ < 300
• If the patient is asymptomatic with chronically mildly
elevated ALT & AST < 100 , and with Negative Viral
Hepatitis, Negative Auto Immune and other metabolic
markers, If nothing suggests serious liver disease
continued follow up is best option
• Liver biopsy : Persistent Aminotransferase more than
double  100 …to clarify the diagnosis , in most
patients  No effective medical therapy
Maddrey's Discriminant Function
Disease Specific Prognostic Score
((Alcoholic Hepatitis))
Mild <----------------------------------> Life Threatening
(4.6 (Bilirubin in mg + ( Patient’s PT – control PT)
Patients who score > 32 are at highest risk of dying with one
month ( mortality as high as 30–50% )
Corticosteroid reduce mortality if ( MDF ) > 32
 Acute Alcoholic injury on a background of alcoholic liver disease ,
may progress to decompensation , precursor of Liver cirrhosis
 ( Fever ~ 101 , RUQ Pain , Elevated PT , Jaundice , Leukocytosis,
Elevated AST > double ALT , Elevated AP & GGT ,Bleeding ,
Encephalopathy … )
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(MELD Scoring )
Model for End-stage Liver Disease
MELD is “ adopted by transplant centers in the US for prioritization of
patients waiting for liver transplant “
MELD Scoring :
“ chronic liver disease severity to predict survival “
Variables are (Bilirubin , INR , Creatinine )
MELD Score = 3.8[Ln serum Bilirubin (mg/dL)] + 11.2[Ln INR] + 9.6[Ln
serum Creatinine (mg/dL)] + 6.4
( Ln is natural logarithm)
The higher the MELD score
The worse is the hepatic function and the higher 3-month mortality risk
Score - Mortality
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40 + — 71.3%
30–39 — 52.6%
20–29 — 19.6%
10–19 — 6.0%
< 9 — 1.9%
Child - Pugh score ( for severity of liver disease )
Child - Pugh Classification
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Albumin, Bilirubin, Encephalopathy , Ascites & INR or Prolonged PT
Points are assigned to each variable  Score Calculated.
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Class One : 5-6 Points , Class B :7-9 Points , Class C : 10-15
Measure
1 point
2 points
3 points
Bilirubin
<2
2–3
>3
Albumin
>3.5
2.8 - 3.5
< 2.8
INR
<1.7
1.7 - 2.3
> 2.30
Ascites
None
Mild
Moderate to Severe
Encephalopathy
None
Grade I-II
Grade III-IV
Ammonia
Nitrogenous compound (ingested protein) enter the colon  degraded by
bacteria  ammonia  absorbed and transported via the portal vein to
the liver  converts to glutamine / urea and excreted.
In diseased liver with Porto systemic shunt , the diseased liver does not clear
ammonia, Blood ammonia increases , which enters the systemic circulation  contributes to hepatic encephalopathy.
May Increase Ammonia Levels:
High-protein meals , GI bleeding , Muscle wasting , CKD, UTI with a ureaseproducing organism , Certain drugs ( Chemo, alcohol, valproate, diuretics,
barbiturates and opioids)
False High Ammonia : ( Hemolysis , Sample not chilled or iced , exposure to
room temperature, delayed processing )
Serum Alpha-Fetoprotein
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AFP : Glycoprotein produced the yolk sac and liver during fetal
development .
AFP in fetus decreases after birth to adult levels by 12 months.
Normal ( Less than 10 or 20 ng/L. )
In HCC : AFP is elevated > 500 ( > 1000 )
Other causes of elevated AFP : Pregnancy and pure Seminoma
Malignancy: Non seminoma Germ cell Tumors
Testicular Cancer ,Gastric , Biliary and Pancreatic cancer
Benign causes : Chronic liver disease without HCC
( Cirrhosis, Acute or Chronic Viral Hepatitis )
AFP > 500 mcg/L In patient with chronic liver disease ( Cirrhosis )
Always HCC is a concern .
HCC has been diagnosed at lower AFP level .
small HCC  ? normal AFP
U/S : Q 6 months if suspicious
 Contrast CT or MRCP
Liver biopsy
• Indication: Undiagnosed liver abnormality /disease
• Small sample obtained , useful if “ diffuse liver changes “
• Provide histologic info , type and degree of liver injury and
diagnosis
• Assess staging , prognosis and helps with mgmt.
• Relatively Safe 98 % , U / S Guided , bedside, local anesthesia
• Limitation: sample error , pathologist experience
• C/ I : Bleeding disorder, suspected vascular lesion…
• Biopsy :
• During surgery , Laparoscopy
• Transcutaneous
• Trans jugular  IVC  Hepatic Vein Liver
Imaging
o U/S : Safe, Cheap, Non invasive , provides Structural NOT
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Functional information .
Best and most sensitive for Biliary System especially GB
Initial Imaging of choice :
Screening Biliary Tract Abnormality
RUQ Pain :Evaluate Hepatobiliary tract and detect liver masses
Initial imaging for Cholestasis : intra or extra hepatic ?
Splenomegaly size  Portal HTN
Limitation: Obesity, Excessive Gas , Operator experience
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U/S : Trans Abdominal
Endoscopic U/S (U/S transducer on the tip of the endoscope )
U/S :
• Gall Stones : Thick GB wall > 3mm
Pericholecystic fluid
Impacted stone in GB neck, sludge
U/S murphy’s .
 Obstruction : Extra hepatic  dilated CBD …
 Diffuse disorders : Cirrhosis & Fatty liver
 Liver lesions: Focal lesions > One Cm +
• Cystic  Echo Free
• Solid Masses :  Echogenic - Abscess or Tumor (HCC or Mets )
• CT:
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Small Liver Metastasis
with iv contrast  Hemangiomas
Fatty liver : Decreased Hepatic Attenuation
Assess Pancreas
MRI : without contrast : Images the blood vessels , ducts and
hepatic tissue . Superior to CT and U/S for Dx Fatty liver (
Increased Fat Signal ) and for Hemochromatosis ,vascular
abnormalities and Hemangiomas.
MRCP: CBD abnormality esp. stones
ERCP : Diagnose : Obstructive jaundice ,Chronic Pancreatitis ,
pancreatic tumor , Gallstones with dilated CBD , Bile duct tumor
and suspected injury to bile ducts .
Replaced by MRCP and Endoscopic U/S
Invasive …Rarely performed without therapeutic intention.
ERCP
Endoscopic retrograde cholangiopancreatography
• Endoscopy  stomach  second part of duodenum …The papilla
of Vater is Cannulated , contrast injected into biliary and
pancreatic duct …detailed images to diagnose obstructing bile duct
and pancreatic duct problems , Obstructive Gall Stones,
Inflammatory Strictures , Scars , Traumatic Leakage , Ampullary
Cancer and can obtain tissue biopsy . It can remove obstructing
stones , dilating and /or stenting strictures PSC , and
Sphictrerotomy for sphincter of oddi dysfunction
• Morbidity : with Diagnostic ERCP s 1% …
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with Sphictrerotomy up to 9 %
• Complication :
• Pancreatitis, Bleeding, Perforation, Cholangitis &
Cholecystitis
• Pancreatitis risk is less with pancreatic stenting