1. health and fitness
2. disease

Abnormal LFTs
Michele Ritter
Argy Resident – February, 2007
Liver Function Test
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Albumin
Bilirubin:
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Serum aminotransferases
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Total Bilirubin
Direct Bilirubin (conjugated bilirubin)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline Phosphatase
Prothrombin time
Albumin

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
Synthesized in the liver
Production is controlled by multiple factors
including nutritional status, serum oncotic
pressure, cytokines, and hormones
A serum albumin may be reflection of the
synthetic function of the liver.
Bilirubin
Bilirubin


Used to determine liver’s ability to clear
endogenous/exogenous substances from the
circulation
Indirect (unconjugated) bilirubin


Direct (conjugated) bilirubin


Elevated with hemolysis, hepatic disease
Elevated with biliary obstruction and hepatocellular
disease.
Jaundice usually develops with a bilirubin ≥ 3
mg/dL
Biliary Tract
Aminotransferases


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Hepatic enzymes that are usually
intracellular, but are released from
hepatocytes with hepatocellular injury.
Includes aspartate aminotransferase (AST)
and alanine aminotransferase (ALT)
AST/ALT ratio


Normal is 0.8
In alcoholic hepatitis, is usually > 2
Alkaline Phosphatase



A group of enzymes that catalyze the hydrolysis of a large
number of organic phosphate esters.
In liver, believed to play an active role in down-regulating the
secretory activities of the intrahepatic biliary epithelium
Found in:
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Liver
Bone
intestine
First trimester placenta
Kidney
Gamma-glutamyl transpeptidase (GGT):


Liver origin: Elevated GGT
Bone origin: Normal GGT
Prothrombin Time (PT)

Liver is in charge of the synthesis of many clotting
factors :







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Factor I (fibrinogen)
Factor II (prothrombin)
Factor V
Factor VII
Factor IX
Factor X
Factors XII and XIII
Elevated PT may be reflection of decreased
synthetic activity of liver.
Assessing the patient with abnormal
Liver Function Tests
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

Most of the time, the cause of elevated LFTs can
be illicited without invasive testing (biopsy)
If no cause of abnormality is found, most
frequently the cause is alcohol liver disease,
steatosis, or steatohepatitis
Certain patterns exist with LFTs
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Hepatocellular Injury: Very high AST, ALT with
mild/moderately elevated alkaline phosphatase.
Cholestatis: mild/moderately elevated AST/ALT with very
high alkaline phosphatase
Bilirubin can be elevated with both combinations.
Hepatocellular Injury

Medications:


History: Need to assess temporal relationship with drug, see if
patient improves once medication removed
NSAIDs, antibiotics, statins, anti-tuberculosis medications,
anti-epileptic drugs, acetaminophen


Acetaminophen overdose

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Frequently cause isolated elevated aminotransferases
Toxicity is likely to occur with single ingestions greater than 250
mg/kg or those greater than 12 g over a 24-hour period
AST/ALT elevations is first sign of liver damage (usually 24-hours
after ingestion)
Alcohol Use:
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Frequently have AST:ALT ratio ≥ 2:1
History: Need accurate assessment of alcohol intake, including
CAGE questions.
Hepatocellular Injury
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Hepatitis A:
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Hepatitis B:
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Can be acute or chronic
History: See if patient from Asia, Subsaharan Africa; Sexual history, Drug use
Labs: Hepatitis B surface antigen, surface antibody, core antibody
Hepatitis C:
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Acute infection
History: travel, recent outbreak, MSM; nausea, vomiting, jaundice
Labs: Hepatitis A IgM, frequent elevated bilirubin
History: IV drug abuse, blood transfusion prior to 1992, Sexual history, Tattoos
Labs: Hepatitis C antibody (Hepatitis C viral load if HIV positive or
immunocompromised)
HIV:
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Often causes isolated elevated aminotransferases
History: Sexual History, IV drug use
Labs: HIV Antibody test (ELISA with reflex Western Blot)
Hepatocellular Injury
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Hereditary Hemochromatosis
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History: Family history of liver disease? Diabetes? Heart
Failure? Bronze skin?
Labs:
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Serum iron, TIBC
 Calculate iron saturation = serum iron/TIBC
 If iron saturation > 45%, check ferritin

Ferritin
 If > 400 ng/mL in men, or > 300 ng/mL in women, then need to check
liver biopsy or genetic testing

Liver biopsy
 Homozygous hereditary hemochromatosis if iron index > 1.9
 If under age 40, and positive genetic testing, no biopsy needed.

Genetic Testing
Hepatocellular Injury
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Hepatic steatosis/Non-alcoholic
steatohepatitis (NASH)
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Increase in AST/ALT are usually less than 4-fold.
Ratio of AST/ALT is usually < 1
History: Female, obesity, diabetes
Labs:
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Labs to rule out other causes of hepatitis
Abdominal Ultrasound: look for fatty infiltration of
liver
Hepatocellular Injury
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Autoimmune Hepatitis
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History: Young to middle-aged female
Labs:
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Serum protein electrophoresis (SPEP) – if
polyclonal increase in gamma globulin
Anti-nucleur antibody: Positive
Anti-smooth-muscle antibody (SMA)
Liver biopsy: should be performed if the above
are negative, but autoimmune hepatitis still
suspected.
Hepatocellular Injury
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Alpha-1-antitrypsin deficiency
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History: Family history, emphysema,
young age
Labs:
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Alpha-1-antitrypsin level/phenotype
Treatment:
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Intravenous alpha-1 antiprotease helps
with lung disease, but liver transplant is
ultimately only treatment for liver
disease.
Hepatocellular Injury
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Wilson’s Disease
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A genetic disorder of biliary copper excretion
History: Age (usually age 5 – 25, but up to age 40), family
history of liver disease; neuropsychiatric disease
Evaluation:
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Serum ceruloplasmin: Low
Opthalmologist: Exam for Kayser-Fleisher rings
24-hour urine copper
Liver biopsy: Evaluate liver copper levels
Treatment:
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Copper chelating agents
Zinc
In some cases, ultimately liver transplant
Wilson’s Disease – Kayser-Fleisher
Rings
Hepatocellular Injury
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Shock Liver (ischemic hepatitis)
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Etiology: Shock, severe hypotension
Severely elevated AST/ALT (50 times normal)
Treatment: Re-establish good blood
pressure/perfusion.
Prognosis: Usually patients recover, but can
progress to fulminant liver failure requiring
transplant.
Hepatocellular Injury
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Non-Hepatic Causes
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Usually only mild increase in AST/ALT
Muscle disorders
Hypothyroidism/Hyperthyroidism
Celiac Disease
Adrenal Insufficiency
Anorexia nervosa
Hepatocellular Injury

What if work-up is negative and AST/ALT
remain elevated?
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Observe:
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Patients with two-fold or less increase in AST/ALT
and no hyperbilirubinemia
Liver Biopsy
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Patients with > two-fold increase in AST/ALT, or
abnormalities of other liver function tests.
Cholestatic Pattern
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Predominantly elevated alkaline phosphatase
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Need to check GGT to see if bone or liver in origin
Blood types O and B: can have elevated serum
alkaline phosphatase after eating a fatty meal due
to an influx of intestinal alkaline phosphatase
Need to determine if the cholestasis is
intrahepatic or extrahepatic in origin.
Cholestatic Pattern - Intrahepatic
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Drugs:
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Anabolic steroids, contraceptives,
antibiotics
Total parenteral nutrition (TPN)
Cirrhosis:
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Viral hepatitis (Hepatitis B, C)
Alcohol hepatitis
Cholestatic Pattern - Intrahepatic
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Primary Biliary Cirrhosis
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Autoimmune disease
Predominately in women, usually ages 35-65
May have history of other autoimmune disease
Symptoms: Prurutis, fatigue, hyperpigmentation,
musculoskeletal complaints
Labs:
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RUQ Ultrasound
Anti-mitochondrial antibody
Liver biopsy to verify diagnosis
Cholestatic Pattern – Both Intrahepatic
and Extrahepatic
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Primary Sclerosing Cholangitis
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chronic progressive disorder of unknown etiology that is characterized by
inflammation, fibrosis, and stricturing of medium size and large ducts in the
intrahepatic and extrahepatic biliary tree
~ 90% have inflammatory bowel disease, especially ulcerative colitis
Symptoms: Pruritus, fatigue, RUQ pain
Diagnosis:
 Ultrasound
 Cholangiogram: multifocal stricturing and dilation of intrahepatic and/or
extrahepatic bile ducts
Prognosis:
 Poor; average life expectancy after diagnosis is ~12 years
 10-15% risk of developing cholangiocarcinoma
 Liver transplant is ultimate only treatment
Cholangiogram of Primary Sclerosing
Cholangitis
Cholestatic Pattern - Extrahepatic
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Choledocholithiasis (gall stones!)
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History:
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The 3 F’s
RUQ colicky abdominal pain
Diagnosis/Treatment: Ultrasound, ERCP (to remove stones)
Malignancy
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Cholangiocarcinoma
Pancreatic
Metastatic cancer
Diagnosis: Ultrasound, MRCP
Treatment: ERCP, biliary stent
Cholestatic Pattern - Extrahepatic
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Chronic Pancreatitis
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History: Recurrent pancreatitis
Symptoms: Abdominal pain, frequently referred to back
HIV Cholangiopathy
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Usually seen in AIDS patients with CD4 count well below
100/mm3
Usually caused by: Cryptosporidium. Microsporidium, CMV
Symptoms: RUQ pain, Diarrhea, Occassional fever,
Occassional jaundice
Diagnosis:
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ERCP
Cholangiography – shows multifocal strictures of extrahepatic
biliary tree
Isolated Hyperbilirubinemia
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Unconjugated (indirect) hyperbilirubinemia
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Overproduction of bilirubin
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Hemolysis
Dubin-Johnson Syndrome and Rotor Syndrome
Decrease in uptake, conjugation, or excretion of
bilirubin
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Increased unconjugated (indirect) bilirubin
Liver Disease
Isolated Unconjugated
Hyperbilirubinemia
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Drugs
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Gilbert’s Disease
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Probenecid, Rifampicin
Autosomal recessive disorder
3 to 7 % of population
Most common in white males
Jaundice, increased unconjugated bilirubin (always < 6)
Occurs when patient under stress/infection
Crigler-Najjar type II
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Caused by gene mutation
Reduced activity of Bilirubin UDP glucuronosyl
SUMMARY
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Hepatocellular Injury –
mostly  AST/ALT

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Drugs
Alcohol hepatitis
Hepatitis A
Hepatitis B
Hepatitis C
Steatohepatitis (NASH)
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Autoimmune hepatitis
Wilson’s Disease
Hereditary
Hemochromatosis
Alpha-1 antitrypsin
deficiency
SUMMARY
Cholestatic Pattern
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INTRAHEPATIC
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Drugs
Hepatitis A, B, C
Alcoholic hepatitis
TPN
Primary Sclerosing
Cholangitis
Primary Biliary Cirrhosis
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EXTRAHEPATIC
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Gall stones
Primary Sclerosing
Cholangitis
Malignancy
Chronic pancreatitis
HIV cholangiopathy
SUMMARY
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Isolated elevated indirect (unconjugated)
bilirubin

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Hemolysis
Drugs
Gilbert’s Disease
Crigler-Najjar type II
Scenario # 1
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A 43-year old woman who has consumed a pint of
80-proof whiskey daily for 18 years presents with
right upper quadrant pain. The pain began
approximately a week ago and has been
transiently relieved by her taking two extrastrength acetaminophen tablets every 4 hours for
the past 4 days. She has had some nausea and
vomiting but no fever. There is no history of
jaundice or cholelithiasis. The patient used
intravenous drugs and shared needles during her
late teen years.
Scenario # 1
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Physical Exam

Enlarged tender liver that percusses to 17 cm in
the right midclavicular line and a tattoo on the
right buttock
Labs:
 Bilirubin: 2 mg/dL AST: 3800
Alk. Phos: 198
PT: normal

Scenario #1

The most likely diagnosis is:
(A) Alcoholic hepatitis
(B) Acute cholecystitis
(C) Acetaminophen hepatotoxicity
(D) Acute viral hepatitis B
(E) Acute viral hepatitis C
Scenario # 2

A 54-year old asymptomatic man volunteers to
donate blood and is found to have elevated
aminotransferase levels. He has no known
medical problems and no history of hepatitis. He
drinks no alcohol, takes no medications, and has
not seen a physician in more than 10 years. He is
active, works as a truck driver, and has noted no
change in his physical condition. He has no
family history of liver disease.
Scenario # 2
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Physical Exam:
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Labs:
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Obesity – Ht: 5’ 10”, 115 kg
AST: 45 ALT: 85 Alk. Phos: 90
Hepatitis serologies (A, B, C): negative
ESR: normal ANA: negative
Smooth muscle antibody: negatie
Total chol: 260 LDL; 225 Triglycerides: 830
Liver biopsy:

Large-droplet steatosis without significant inflammatory reaction
and no fibrosis. Ultrasonography shows a mildly enlarged fatty
liver.
Scenario # 2

The appropriate management of this patient
would be:
(A)
(B)
(C)
(D)
(E)
Interferon therapy for presumed chronic non-B, non-C
hepatitis
Alcohol rehabilitation and counseling
Weight loss and therapy for hyperlipidemia
Endoscopic retrograde cholangiopancreatography
(ERCP) to evaluate the biliary tree
Corticosteroid therapy
Scenario # 3
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A 43-year old woman complains of itching that
keeps her awake at night. Physical examination
is normal except for the liver, which is felt 7 cm
below the right costal margin.
CBC is normal
Creatinine: 0.8 mg/dL, Bilirubin: 0.6 mg/dL
ALT: 78 U/L, Albumin: 4.2 g/dL
Alkaline Phosphatase: 450 U/L
Cholangiogram: normal
Scenario # 3

Which test would be most accurate in
diagnosing her underlying disorder?
(A) Serum protein electrophoresis
(B) Anti-Smooth Muscle Antibody
(C) Antimitochondrial antibody
(D) Technetium-99m liver-spleen scan
(E) Endoscopic retrograde
cholangiopancreatography (ERCP)