Approach to Abnormal LFT

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Approach to Abnormal LFTs

• By
• William E. Stevens, MD

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Abnormal LFTsEpidemiology

• 0.5 of 19,877 healthy air force recruits have an
  LFT abnormality
• Alcohol, HCV, and steatosis are the most common
  causes of abnormal LFTs
• Diagnosis can be established noninvasively in
  most cases

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Approach to Abnormal LFTs

• The biochemical LFTs AST, ALT, ALK PHOS,
  BILI GGT, 5NT, LDH ALB, P.T.
• Abnormal LFT syndromes Severe vs. mild
  elevations Acute vs. chronic elevations
• Hepatitic vs. cholestatic pattern

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The AminotransferasesAspartate aminotransferase
(AST)Alanine aminotransferase (ALT)

• Participate in gluconeogenesis catalyzing
  transfer of amino groups to aketoglutarate
• AST found in liver, heart and skeletal muscle,
  brain, kidney, pancreas, lungs, WBCs, and RBCs
• ALT found primarily in liver
• Elevations occur due to hepatocyte membrane
  damage
• Almost all hepatobiliary diseases to some degree
  cause elevation
• The higher the ASTALT ratio, the more specific
  for ETOH related liver disease
• ASTALT gt21 is 90 specific for ETOH injury
• ASTALT gt31 is 97 specific for ETOH injury

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Alkaline Phosphatase

• Ubiquitous isoenzyme family found in liver, bone,
  placenta, kidney intestine, WBCs
• Slight elevations can occur normally in blood
  type O and B, after fatty meals, and increase
  with age
• Isolated mild transient elevations are common,
  resolve spontaneously, are associated with no
  pathology
• Abnormally low levels occur in hypothyroidism,
  pernicious anemia, zinc deficiency, Wilsons
  disease
• High elevations imply cholestasis due to
  intrahepatic, extrahepatic or infiltrative
  processes
• Elevations occur due to enzyme induction and
  synthesis, levels may be normal with acute
  biliary obstruction

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Gamma Glutamyl Transpeptidase (GGT)

• Found in liver, biliary epithelium, spleen,
  pancreas, heart, lung, brain. Not found in bone
• Primarily useful in confirming hepatic origin of
  an elevated alkaline phosphatase
• Induced by ETOH, anticonvulsants, coumadin, etc
• Most sensitive indicator for hepatobiliary
  disease
• Very nonspecific not very useful

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5 Nucleotidase (5 NT)

• Found in liver, biliary epithelium, intestine,
  brain, heart, pancreas
• Very specific for hepatobiliary disease
• Levels correlate closely with alkaline
  phosphatase
• Useful in confirming hepatic origin for elevated
  alkaline phosphatase

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Lactate Dehydrogenase (LDH)

• Widespread, ubiquitous isoenzyme
• Elevations are due to cellular necrosis
• Massive elevations are suggestive for ischemic
  necrosis
• Limited diagnostic utility

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Albumin

• Liver synthesizes 10 gm/d
• Serum half life is 20 days
• Synthetic ability and serum levels decrease with
  progressive liver disease
• Levels vary depending on nutritional status,
  volume status, vascular integrity, catabolism,
  urine and stool losses
• Low levels are not specific for liver disease

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Pro Time (PT)

• Liver synthesizes Factors I, II, VII, IX, X, and
  degrades FDPs
• Elevations of PT are not specific for liver
  disease
• Elevations that are due to liver disease are good
  indicators for severity of liver disease

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Bilirubin

• Derived from catabolism of hemoglobin
• Two forms water soluble--conjugated--dire
  ct water insoluble--unconjugated--indirect
• Direct bilirubin increases due to defects in
  hepatic bilirubin excretion biliary obstruction
  or hepatocellular disease
• Indirect bilirubin increases due to increased
  hemoglobin breakdown or defects in hepatic uptake
  or conjugation

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Evaluation of Abnormal LFTs

• Do a history some liver diseases are more
  common in certain ages and genders Age
  lt40 Autoimmune, Wilson's Dis gt40
  NASH, Hemochromatosis, Biliary
  obstruction Sex male Hemochromatosis,
  PSC female Autoimmune, PBC

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Evaluation of Abnormal LFTsDo a history

• How long have they been abnormal?
• How much Alcohol?
• Any risk factors for viral hepatitis IVDA,
  blood transfusion, tattoos, intranasal cocaine,
  multiple sex partners, multiple body piercing
• Autoimmune symptoms rashes, arthralgias,
  myalgias, thyroid problems, Sjogrens symptoms
• Weight changes, anorexia
• Cholestatic symptoms RUQ pain, fever, chills,
  pruritus, jaundice, dark urine, light colored
  stools
• Review medications, herbs, OTC medications

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Evaluation of Abnormal LFTsDo a physical exam

• Spider angiomas
• Enlarged liver and spleen
• Abdominal tenderness
• Findings of cirrhosis ascites, edema,
  encephalopathy, palmer erythema, gynecomastia,
  testicular atrophy, caput medusa
• Cardiac exam, heart murmurs, JVD

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Abnormal LFT Syndromes

• Isolated elevation of Bilirubin
• Elevations of Alkaline Phosphatase and Bilirubin
  Cholestasis
• Massive elevations of AST / ALT
• Mild chronic elevations of AST / ALT

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Approach to an Isolated Elevation of Bilirubin

• Elevations occur from
• Bilirubin overproduction
• Impaired bilirubin uptake, conjugation, or
  excretion
• First fractionate bilirubin conjugated vs.
  unconjugated
• Unconjugated hyperbilirubinemia
• Increased bilirubin production
• hemolysis, hematoma, dyserythropoiesis (check
  haptoglobin)
• Impaired bilirubin conjugation
• Gilberts Syndrome 3-7 population, increased
  in white males, Bili lt6
• Chronic liver diseases, advanced cirrhosis,
  Wilsons Disease, estrogens
• Crigler-Najjar syndrome types I and II, extremely
  rare
• Impaired hepatic bilirubin uptake
• rifampin, probenicid, CHF, etc.
• Conjugated hyperbilirubinemia
• Dubin-Johnson Syndrome abnormal excretion of
  bilirubin into bile ducts
• Rotor Syndrome defective intrahepatic storage
  of bilirubin
• Both very rare asymptomatic jaundice in 2nd
  decade of life

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Approach to CholestasisElevations of Alkaline
Phosphatase and Bilirubin

• History abdominal pain, fever, pruritis,
  jaundice, medications, ?IBD
• If isolated Alk Phos elevation confirm liver as
  source with 5NT, GGT or Alk Phos isoenzymes
• Ultrasound
• If US is abnormal
• Biliary obstruction CBD stones, strictures or
  biliary and pancreatic malignancies
• Hepatic malignancy
• If US normal
• Consider medications steroids, erythromycins,
  chlorpromazine, etc.
• TPN, sepsis, post-operative cholestasis,
  intrahepatic cholestasis of acute illness
• PBC, PSC, Vanishing bile duct syndrome
• Infiltrative diseases, steatosis/NASH, sarcoid,
  granulomatous liver disease
• If Alk Phos is lt1.5 x abnormal and US is normal,
  and patient is asymptomatic, then serial follow
  up is reasonable
• Otherwise, check AMA, consider MRCP, then Liver
  Biopsy or ERCP

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Primary Biliary Cirrhosis

• Median age 50, FemaleMale 91
• presents with fatigue, pruritis
  hepatospleenomegaly
• AMA 95
• Liver biopsy ductopenia with inflamed damaged
  intrahepatic bile ducts, granulomas, biliary
  cirrhosis
• Treatment manage osteoporosis, osteomalacia,
  fat soluble vitamin deficiency, pruritus,
  cholesterol, steatorrhea
• Ursodeoxycholic acid

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Approach to Massive AST/ALT Elevations (gt2000)

• Limited differential diagnosis
• Drugs/Toxins Tylenol, ETOH Tylenol, other
  idiosyncratic reactions, mushrooms, herbs
• Acute Viral Hepatitis A,B,C,D,E, HSV, Giant
  Cell virus, others
• Ischemic Hepatitis hypotension, CHF,
  arrhythmias, cocaine
• CBD Stone
• Autoimmune Hepatitis

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Approach to Mildly Abnormal AST /ALT100
Consecutive Blood Donors with Mildly Abnormal ALT

• Findings after H P, serologies and ultrasound
• 48 ETOH
• 22 Fatty Liver
• 17 HCV
• 4 other
• 9 no identifiable explanation

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Mildly Abnormal LFTsLiver Biopsy Findings

• 81 with chronically abnormal LFTs and negative
  H P and serologic evaluation
• 84 Hepatic steatosis or NASH
• 6 advanced fibrosis or cirrhosis
• 8 normal
• Summary
• Most etiologies are identified by history,
  physical, basic serologies or ultrasound
• Most cases still with diagnostic uncertainty are
  due to ETOH or Hepatic Steatosis / NASH
• Liver Biopsy aides management in 18
• Complication rate of liver biopsy 1-3
• Severe complications occur in 0.1

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Causes of Mild Chronic Elevation of AST/ALT

• Hepatic causes ETOH Medications,
  herbs Hepatitis C and B Steatosis and
  NASH Autoimmune hepatitis Hemochromatosi
  s Wilsons disease Alpha-1-antitrypsin
  deficiency
• Nonhepatic causes Celiac sprue CHF T
  hyroid and Adrenal disease Muscle diseases
  and strenuous exercise

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Laboratory Tests in Asymptomatic patients with
Mild Chronically Elevated AST/ALT

• Primary tests Repeat LFTs HCV antibody
  HBV Surface antigen HBV Surface
  antibody HBV Core antibody Transferrin
  saturation, ferritin
• Secondary tests ANA, ASMA
  Ceruloplasmin (agelt40) Alpha-1-antitrypsin
  phenotype Ultrasound

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Alcohol Related Liver Disease

• 14 million alcoholics in U.S.
• 2 million in U.S. with alcohol related liver
  disease
• gt14,000 liver related deaths per year due to
  alcohol
• prevalence is higher in men women are more
  susceptible to liver injury
• risk of liver injury increases with consumption
  of over 30 gm/d ETOH only 10 who consume over
  80 gm/d get liver disease
• ASTALT gt2-31 GGT gt2x elevated
• AST and ALT usually less than 300

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Hepatic Steatosis and NASH

• Most common cause of unexplained abnormal LFTs
• 25 ultrasounds in U.S. show fatty liver
• Likelihood for advanced disease increases if
  age gt40, Type 2 Diabetes Mellitus, Obesity,
  Hyperlipidemia
• May have RUQ pain, hepatosplenomegaly
• ASTALT (usually), levels usually lt200
• Consider liver biopsy for diagnosis and staging.
  Liver biopsy looks like alcoholic hepatitis
• Treatment weight loss, improve DM and lipid
  control, stop ETOH, ?ursodeoxycholic acid,
  ?metformin, ?Vit E

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Viral Hepatitis C and B

• Hepatitis C 3-4 million in U.S 90
  have risk factors, 30 have normal LFTs HCV
  antibody is 97 sensitive HCV RNA PCR is
  confirmatory test Treatment PEG interferon
  Ribavirin
• Hepatitis B 1 million in
  U.S. Increased in homosexuals, African and
  Asian immigrants, HCV risk factors HBV S
  Ab, HBV Core Ab immunity, prior
  disease HBV S Ag presence of
  disease HBV E Ag or HBV DNA active
  viral replication, infective Treatment PEG
  interferon, or Lamivudine, Adefovir, Entecavir
  

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Hemochromatosis

• Primary genetic hemochromatosis 1/200 (0.5)
  Caucasians
• Secondary hemochromatosis due to chronic
  hemolysis
• May have RUQ pain, arthritis, impotence,
  diabetes, hepatomegaly, skin pigmentation
• Transferrin Saturation gt45, elevated Ferritin
• HFE testing C282y, H63d mutations account for
  90 10 Caucasians are heterozygotes
• Liver Biopsy if Agegt40, abnormal LFTs, Ferritin
  gt 1000, uncertain diagnosis
• Treatment Phlebotomy every 1-2 weeks until iron
  depleted then 2-6 times per year

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Medication Induced Abnormal LFTs

• Almost any medication can cause abnormal LFTs
• Ask when medications were started OTC
  medications, herbal preparations
• Stop probable offending medications
• Risk/Benefit analysis if medication must be
  continued. Liver Biopsy may be helpful.

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Medications that Cause Elevated LFTs

• Antibiotics penicillin's, mycin's, floxicins,
  nitrofurantoin, keto and fluconazole, INH
• Antiseizure dilantin, tegretol, valproic acid
• Statins and Niacin
• NSAIDs diclofenac
• Sulfonylureas glypizide
• Vitamin A
• Herbs germander, chaparral, mahuang, gentian
• Drugs ecstasy, cocaine, PCP, glues, solvents

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Autoimmune Hepatitis

• 150,000 in U.S. femalemale, 4-61
• 40 have other autoimmune diseases thyroid, RA,
  UC, Sjogrens,
• ANA, ASMA 70
• Elevated Ig G
• Treatment prednisone imuran

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Wilsons Disease

• Wilsons disease gene facilitates biliary copper
  excretion.
• Age of onset 6-40
• Various presentations Hepatic fulminant
  liver failure chronic active
  hepatitis Neurologic movement
  disorder rigid dystonia Psychiatric neuro
  ses, depression
• Diagnosis low ceruloplasmin, high 24 hour urine
  copper, liver biopsy, Kayser-Fleischer rings
  present in 95
• Treatment Penicillamine, Trien, Zinc

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Alpha-1-Antitrypsin Deficiency

• Protease inhibitor inhibits neutrophil elastase
  modulating inflammatory cascades
• 1/1500 Caucasians
• Abnormal phenotype causes retention of A-1-AT in
  hepatocytes
• Normal MM most abnormal ZZ other
  variants MZ, MS, SS, SZ
• Neonatal or childhood cholestatic hepatitis
• In adults emphysema and cirrhosis

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Asymptomatic Patients with Abnormal ALT and
Negative Serologic Evaluations

• 1124 patients with chronically elevated ALT
• 81 patients had NEGATIVE serologic evaluations
• All had Liver Biopsy. Findings 41 fatty
  liver 26 NASH 4 fibrosis with fatty
  liver 2 cirrhosis with fatty liver 8 normal

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Mild Elevations of LFTsEpidemiology

• 19,877 Air Force recruits
• 99 (0.5) had ALT gt55
• Only 12 (12) had a cause identified
• HBV, HCV, Autoimmune, Gallstones
• 88 no identifiable cause identified

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Hepatobiliary Syndromes

• Hepatitic pattern elevated AST, ALT
• Cholestatic pattern elevated Alk Phos, Bili
• Acute versus chronic elevations
• Massive versus mild elevations