Gastroenterology and Hepatology - Abnormal LFTs

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    Evaluation of Liver

    FunctionAbnormalities

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    Goals:

    Know the treatable causes of liver disease. Understand the 3 patterns of abnormal LFTs. Know the differential diagnosis of LFT

    abnormalities. Be able to select appropriate diagnostic tests.

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    TreatableChronic Liver Diseases

    Hemochromatosis

    Wilsons disease

    Autoimmune hepatitis Hepatitis C

    Chronic hepatitis B

    Drug hepatotoxicity NAFLD/NASH

    Celiac sprue

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    Abnormal LFTs:

    3 Patterns

    1. Hepatocellular:

    AST and ALT > 2x normal.2. Hepatocanalicular: mixed

    transaminases and alk phos elevated > 2x

    normal.3. Canalicular/Cholestatic:alk phos and bilirubin elevated > 2x normal.

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    Hepatocellular

    AST and ALT levels:1.5-3 x normal

    80-180

    4-7 x normal

    200-400

    > 10 x normal

    800-10,000

    Alcohol

    NAFLD/NASH

    Medications

    Chronic Hepatitis C, BHemochromatosis

    Autoimmune CAH

    A1AT deficiency

    Celiac sprue

    Alcohol

    Alcoholic Hepatitis

    NASH

    MedicationsChronic Hepatitis C, B

    Autoimmune CAH

    Wilsons disease

    Tylenol

    Alcohol + Tylenol

    Acute Hepatitis:

    A, B, CAutoimmune CAH

    Ischemia

    Medications

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    Alcoholic Hepatitis

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    Alcoholic Hepatitis: Lab

    AST, ALT and alk phos are elevated.

    AST and ALT < 500.

    AST two-fold higher than ALT.

    Leukocytosis.

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    Alcoholic Hepatitis:

    Prognosis

    Maddrey discriminant function:

    (4.6 x [PT control PT]) + (serum bilirubin). DF > 32 high short-term mortality 35% one month mortality without encephalopathy

    45% with encephalopathy

    MELD score. MELD > 11 performs as well as DF. MELD > 21 predicts a 75% 90-day mortality.

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    Alcoholic Hepatitis:

    Treatment

    Enteral feeding can improve survival. 12 vs. 47% mortality (Cabre, et al. 1990)

    Treat alcohol withdrawal.

    Fluids, calories and vitamins (thiamine, folate, pyridoxine).

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    Alcoholic Hepatitis:Steroids

    12 controlled trials: 5 showing reduced mortality and 7 with no

    difference.

    2/3 meta-analysis show benefit.

    Benefit most evident in severe disease,especially with encephalopathy.

    DF > 32 Prednisolone 40 mg daily forfour weeks, then taper.

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    Mortality about 40%, even with steroids. About 7 patients need to be treated to

    prevent one death.

    Alcoholic Hepatitis:Steroids

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    Inhibits TNF synthesis.

    400 mg po tid. Four week mortality 25% vs. 46%.

    Benefit related to decreased HRS.

    Alcoholic Hepatitis:

    Pentoxifylline

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    NON-ALCOHOLIC FATTY

    LIVER DISEASE (NAFLD)and

    STEATOHEPATITIS (NASH

    )

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    Key Concepts

    NAFLD is the most common cause of chronic liverdisease.

    NAFLD is caused by insulin resistance (IR).

    Spectrum: simple steatosis steatohepatitis.

    NASH: necroinflammation and fibrosis.

    Two-hit hypothesis: IR + oxidative stress.

    TNF-a + adiponectin: central roles in pathogenesis of IR. Treatment: reversal of IR, TNF-a inhibition?

    NAFLD and NASHNAFLD and NASH

    NAFLD: Spectrum of Hepatic Pathology

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    Steatosis

    Steatohepatitis

    Cirrhosis

    Hepatocellular

    carcinoma

    NAFLDSpectrum of Hepatic Pathology

    p p gy

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    NAFLD and the Metabolic Syndrome

    Knobler, et al. Fatty liver-an additional and treatable feature of the

    insulin resistance syndrome. Q. J. Med. 1999;9273-9.

    Marceau, et al. Liver pathology and the metabolic syndrome X in severe

    obesity. J. Clin. Endocrinol. Metab. 1999;84:1513-17.

    NAFLD

    Obesity

    Diabetes Hyperlipidemia

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    Hispanics Whites Blacks

    45%

    33%24%

    Fatty liver

    Prevalence of Hepatic SteatosisVaries with Ethnicity

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    NAFLD PrevalenceGeneral US Adult Population

    Dallas Heart Study (2,200 adults)

    Assessed NAFLD with l iver imaging

    General prevalence of fatty liver 31%(range 24% - 45%)

    Most in div iduals (79%) w ith fatty l iver do no t

    exhibi t am ino transferase elevations

    NHANES III (15, 700 adults)Assessed NAFLD with aminotransferases

    General prevalence of NAFLD 5.5%

    NAFLD Prevalence

    5.5-31%

    3-10 x more

    prevalent than

    Hepatit is C

    Risk Factors for Cirrhosis

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    Risk Factors for Cirrhosis

    Age > 45-50 years

    Obesity Diabetes

    66% p revalence of b r idging f ibrosis

    i f age > 50 years and patient obese

    or diabetic

    s acto s o C os s

    Prevalence of F3-F4 Fibrosis in Common Liver Diseases

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    Prevalence of F3-F4 Fibrosisin Common Liver Diseases

    %

    NAFLD Other

    ObeseGastric bypass

    patients

    OlderDiabetics

    AlcoholAbusers

    ChronicHCV

    0

    50

    75

    100

    25

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    Types of NAFLD:

    Type 1: Fat alone Type 2: Fat + inflammation Type 3: Fat + ballooning degeneration

    cirrhosis 21% Type 4: Fat + fibrosis and/or Mallory

    bodies cirrhosis 28%

    Retrospective study, 136 patients, 98 followed 10 years.

    Matteoni, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.

    Gastroenterology 1999;116:1413-9.

    Prognostic Implications of NASH + Fibrosis

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    More consistent and rapidprogression to cirrhosis than NAFL

    NAFL Cirrhosis

    3%

    NASH +fibrosis

    Cirrhosis30%

    > 10 years

    5-10 years

    Matteon i et al. Gastro entero log y 1999; 116:1413

    Prognostic Implications ofNASH + Fibrosis

    g p

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    Treatment of NAFLD

    Diet

    Exercise

    Weight loss

    NAFLD - What can we do?

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    NAFLDWhat can we do?

    Other approaches unproven

    Specific pharmacotherapy for NAFLD

    Beneficial in preliminary studiesInsulin sensitizers: TZDs > metformin

    Benefit still unproven by preliminary studiesLipid lowering agents: Statins, fibratesAntioxidants: Betaine, SAMe, vitamin E

    Probiotics

    Not beneficialUrsodeoxycholic acid

    NAFLD: Therapeutic Approach

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    Steatosis CirrhosisSteatohepatitis

    Overt Metabolic Syndrome (MS)

    Yes No

    Treat MS

    Rx DMAnti-HTN

    Lower lipids

    Treat NAFLD

    Monitor for NAFLD ProgressionPhysical exams (portal HTN)

    Blood tests (platelets, AST/ALT; fibrotest?)

    Reduced kcals

    Exercise

    Enroll in trial Rx portal HTN

    Screen for HCC

    OLT *

    *Decompensated pat ients without s urgical contra indicat ions

    NAFLD: Therapeutic Approach

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    Drug Hepatotoxicity

    Sulfonamides, PCN, TCN, fluconazole,

    phenytoin, anti-emetics, NSAIDs. Occurs within 2 weeks 12 months ofexposure.

    Fever, pruritus, skin rash, arthralgias,eosinophilia.

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    Viral Hepatitis

    Hepatitis A: IgM ab.

    Hepatitis B: HBsAg.

    Hepatitis C: antibody and PCR.

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    Hemochromatosis

    Affects 1 in 200 people.

    Transferrin saturation > 50%. Ferriten > 1000.

    HFE gene analysis. Biopsy with hepatic iron index.

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    Autoimmune Chronic

    Active Hepatitis Young women. Type 1: ANA, ASMA, aSLA.

    Type 2: aLKM. Increased IgG level.

    Increased g-fraction on SPEP