Elevated Liver Function Tests

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Elevated Liver Function Tests

• Senior talk 2009
• MAISSAA JANBAIN, MD

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BACKGROUND

• Abnormal LFTs are frequently detected in
  asymptomatic patients (1-4).
• They do not always reflect liver diseases.
• They may be a marker of worse health outcomes.

3
BACKGROUND

• A diagnosis can be established noninvasively in
  the majority of cases and usually guided by
  pretest probability as well as the pattern of
  abnormalities.
• A complete history is very important duration,
  degree, associated symptoms and exposure to
  medications, chemicals, alcohol or recent travel
  history.

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Isolated elevation of transaminases1.common
hepatic causes

• Medications (NSAIDs, Anitbiotics, statins,
• antiepileptics and herbal preparations)
• Alcohol (AST/ALT gt21, twofold elevation
• of GGT)
• Hereditary hemochromatosis (Caucasian, iron,
• TIBC, ferritin /- liver biospy)

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Isolated elevation of transaminases1.common
hepatic causes

• Viral hepatitis HBV ( HBsAg, anti HBsAg, anti
  HBc) and HCV ( ELISA, RIBA, PCR )
• Hepatic steatosis and NASH ( AST/ALTlt1,
  ultrasound, CT or MRI)
  

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Isolated elevation of transaminases 2.
Nonhepatic causes

• Muscular disorders (AST/ALTgt3 if immediately
  after injury, CK, LDH, aldoalse)
• Thyroid diseases (TSH)
• Celiac disease (ALTgtAST, reversible with gluten
  free diet)
• Adrenal insufficency ( reversible within week of
  treatment)
• Anorexia nervosa

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Isolated elevation of transaminases 3.Rare liver
diseases

• Wilson s disease (age 5-25, serum ceruloplasmin,
  24hr urine for copper, liver biopsy)
• Autoimmune hepatitis ( SPEP, ANA , SMA, LKMA,
  liver biopsy)
• Alpha 1 antitrypsin (associated emphysema,
  protein electrophoresis)

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Isolated elevation of transaminases 3.Rare liver
diseases

• If no cause was identified and ALT, AST elevation
  is less than tow fold, no more investigations.
• Biopsy is done otherwise eventhough it is less
  likely to provide diagnosis or lead to changes in
  management.

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Isolated Hyperbilirubinemia

• Unconjugated
• Hemolysis (smear, retic count, haptoglobin) can
  be inherited or acquired. Rarely exceeds 5mg/dl
• Impaired uptake or conjugation, drugs, Crigller
  Najjar and Gilberts syndrome.

• Conjugated
• Dubin Johnson with altered excretion
• Rotor syndrome with defective storage.

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Isolated elevation of alkaline phosphatase

• Alk phos is derived from liver, bones, intestins
  and placenta.
• Levels vary with age, more elevated in children.
• To determine the source we check GGT or 5
  nucleotidase.
• Initial evaluation includes U/S and AMA followed
  by ERCP v/s liver biopsy.

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Isolated elevation of GGT

• Very sensisitive for hepatobiliary disease but
  not specific.
• Can reflect pancreatic disease, MI, renal
  failure, diabetes, COPD, alcoholism.

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Cholestasis

• The first step is to obtain ultrasound.
• 2 big categories intrahepatic and extrahepatic.
• Absence of biliary dilatation suggests
  intrahepatic cholestasis.

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Extrahepatic cholestasis

• u/s shows biliary dilatation, and usually is
  followed by ERCP v/s CT scan.
• Choleodocholithiasis is the most common.
• Other causes include malignancies, PSC, chronic
  pancreatitis and HIV cholangiopathy due to CMV or
  cryptosporidium (usually with no jaundice)

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Intrahepatic cholestasis

• Viral hepatitis (A, B, C, EBV, CMV)
• Alcoholic hepatitis
• PBC
• Drugs (anabolic and OCPs, usually reversible)
• Vanishing bile duct syndrome, adult bile
  ductopenia (chronic rejection, sarcoidosis)
• Benign recurrent cholestasis (AR)
• Pregnancy
• TPN, sepsis, post-op, Stauffers syndrome

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Hepatitis A

• RNA virus with 4 genotypes but one serotype.
• Fecal-oral route but also sexual (homosexual!),
  IVDA, and most common in USA international
  travel.
• Incidence has significantly decreased with
  vaccination.

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Hepatitis A

• Usually acute self limited rarely fulminant
  especially if associated with chronic hep C.
• Manifestations vary with age, more silent in
  children.
• Incubation period of 30 days followed by abrupt
  prodromal symptoms then jaundice.
• Extrahepatic manifestations vasculitis, optic
  neuritis, thrombocytopenia, aplastic anemia,
  transverse myelitis.

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Hepatitis A

• IgM anti HAV is the gold standard for diagnosis.
• Start at the onset of symptoms and remain
  positive 4-6 months.
• Infected individuals are contagious during
  incubation and for a week after jaundice appears.
• Handwashing is very important !!! As HAV survives
  for up to 4 hrs on fingertips.

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Hepatitis A

• Treatment is usually supportive.
• Prevention is mainly by good hygiene and
  vaccination ( travel to high risk areas).
• IM Immunoglobulin are available for people
  allergic to vaccine and immunocompromised, they
  provide passive immunity for up to 6 months.

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Hepatitis C
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Hepatitis C

• Flaviviridae family the prototype Hepacivirus
• Rapid replication rate
• High mutation rate that allows him to escape the
  immune recognition.
• Hep C infection can present as acute hepatitis,
  chronic hepatitis, cirrhosis, HCC or extrahepatic

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Hepatitis C

• Incubation period 6-7 weeks and seroconversion
  time 8-9 weeks.
• Acute symptomatic cases occur in 10-30 while
  fulminant hepatitis occurs almost exclusively in
  patients with HBV.
• Most cases progress slowly to chronic infection.
  Mechanism is unknown. Viral, host and other
  factors play role.

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Hepatitis C

• Host factors
• HLA-DRB1, DQB1
• Low peak levels of HCV during acute infection
• Age
• Ethnicity
• Coinfections (HIV, Hep B)
• High BMI

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Hepatitis C

• Viral factors
• Genotype 1B
• Coinfection with gt1 HCV genotype
• Other Factors
• Marijuana
• Alcohol
• Amount of inflammation and fibrosis on liver bx
• Corticosteroids

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Chronic Hepatitis C

• Symptoms if present are nonspecific Fatigue most
  common
• Lack of correlation between symptoms and serum
  enzymes/liver histology.
• ALT is mostly normal to mildly elevated used by
  some to monitor interferon therapy, while others
  are more interested in AST/ALT 1 as predictor of
  cirrhosis.

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Cirrhosis/Complications

• 20-50 (different studies) of chronic infections
  progress into cirrhosis where most complications
  of Hepatitis C are usually confined and survival
  is impaired.
• Hepatic decompensation is manifested usually as
  ascites, followed by varcieal bleeding and
  jaundice
• Hepatocellular carcinoma 0-3 of cases. More with
  genotype 1B
• Once these complications occur, transplant is the
  only effective therapy

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Extrahepatic manifestations

• Hematologic (mixed cryoglobulenimia, lymphoma)
• Renal (membranoproliferative GN)
• Autoimmune (thyroiditis)
• Dermatologic ( porphyria cutanea tarda, Lichen
  palnus)
• Diabetes mellitus.

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Exposure (acute phase)
HIV, HBV, Alcohol
55-85 (55-85)
15-45 (15-45)
Chronic
Resolved
20 (9-14)
80 (44-68)
Cirrhosis
Stable
25 (2-3)
75 (7-11)
Slowly Progressive
HCC Transplant Death
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Hepatitis C Diagnosis

• Who should be tested? AASLD recommendations
• Abnormal ALT
• IVDU hx
• Blood transfusion lt 1992
• Clotting factors lt1987
• Kids to HCV infected mothers
• Current sexual partners to HCV infected subjects
• Needle stick

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Hepatitis C Diagnosis

• Elisa
• RIBA
• PCR-RNA
• Genotype
• Liver biopsy

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Treatment

• Counseling
• Diet NO alcohol
• Smoking controversial
• Zofran for fatigue 4 mg bid
• The mainstay of treatment is Interferon and
  ribavirin
• Goals of treatment
• eradicate HCV infection, slow disease
  progression,
• improve hepatic histology (function) and
• prevent hepatocellullar carcinoma

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Interferon

• Glycoproteins produced by cells in response to
  infection
• Biological properties of interferons
• anti-viral
• immunostimulatory
• anti-proliferative
• anti-angiogenic

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Pegylated Interferon

• covalent attachment of variably configured
  polyethylene glycol (PEG) chains to sites on the
  interferon molecule
• delays absorption
• decreases clearance rate
• allows once per week dosing
• alters properties and activity of parent compound
• prolongs immune activation and cytokine-derived
  antiviral effects
• two pegylated interferons are now FDA-approved
• peginterferon alfa-2a (Pegasys - Roche)
• peginterferon alfa-2b (PEG-Intron - Schering)

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Ribavirin

• guanosine analogue
• active against many viruses in vitro and in vivo
• mechanism of action against HCV unclear
• depletion of intracellular triphosphate pools
• inhibition of viral-dependent polymerase
• immunomodulatory
• mutational deletions

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Indications for treatment

• stage 2-3 fibrosis and/or grade 3-4 necrosis/
• inflammation on liver biopsy
• stage 4 fibrosis (cirrhosis) with compensated
  liver function
• genotype 2 or 3, viral load lt 2 million IU/mL
• severe symptoms related to cirrhosis or
  extrahepatic symptoms (e.g., cryoglobulinemia)
• desire to be pregnant without risk of vertical
  transmission

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Contraindications for treatment

• pregnancy or breast feeding
• unwilling to practice reliable birth control
• anemia (hemoglobin lt11 g/dL)
• uncontrolled cardiac or cerebrovascular disease
• renal failure
• unstable neuropsychiatric disease
• active alcohol or drug use
• allergy or hypersensitivity to IFN or ribavirin

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Recommended Regimen

• genotype 1a/b and 4
• pegylated interferon alfa-2a or 2b (see below)
  plus ribavirin (1000-1200 mg/d) for 48 weeks
• genotypes 2, 3
• pegylated interferon alfa-2a plus ribavirin (800
  mg/d) for 24 weeks
• If viral load does not drop by a factor of at
  least 2 logs within the first 12 weeks of
  treatment, therapy should be discontinued.
• e.g., viral load of 1,000,000 IU/mL must decrease
  to 10,000 IU/mL to indicate an early viral
  response.
• Early viral response (EVR) predicts sustained
  viral response (SVR)

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Investigational Therapies

• Albuferon (longer half life, but same side
  effects and efficacy)
• Thymus an extract of thymus gland
• Interleukin 10, 11
• resiquimod (receptor TLR7)