Laboratory Tests Clinical versus Insurance Medicine

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Laboratory TestsClinical versus Insurance
Medicine

• Zuzanna Guzel MD CMO Allianz, Polska
• Liver enzymes and NASH/ASH
• prognosis
• ICLAM Venice 2004

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Non-alcoholic fatty liver disease NAFLD

• NAFLD has four histological stages
• (1) fatty infiltration of the liver (steatosis)
• (2) fatty infiltration plus inflammation
  steatohepatitis
• (3) fatty infiltration with ballooning
  degeneration
• (4) fatty infiltration with lesions similar to
  alcoholic hepatitis and sinusoidal fibrosis
• advanced fibrosis
• cirrhosis (end-stage liver disease)

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What is Nonalcoholic Steatohepatitis NASH

• described in 1980 by Ludwig
• today recognised as a distinct clinical entity
• characterised by evidence of fatty changes with
  lobular hepatitis and absence of alcoholism
• other terms pseudoalcoholic hepatitis,
  alcohol-like hepatitis, fatty-liver hepatitis,
  steatonecrosis, and diabetic hepatitis
• risk factors obesity, female gender, middle age,
  diabetes, dyslipidemia

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Epidemiology and Associated Conditions

• association with the metabolic syndrome in gt85
  insulin resistance, obesity, hypertension, and
  type 2 diabetes mellitus (hypothyroidism)
• risk factors for NASH, include also
  hyperlipidemia (hypertriglyceridemia type 2b,
  type 4), low HDL-cholesterol, history of
  significant/rapid weight loss or weight gain
  history of consumption of estrogens, androgens,
  extensive abdominal surgery, therapy with drugs
  as amiodarone, tamoxifen, perhexiline maleate,
  glucocorticoids

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Epidemiology and Associated Conditions

• among those with risk factors, NASH is present in
  at least 20 of obese adults or children (BMI
  gt30 kg/m2 or gt 27 kg/m2 in Asians ) with or
  without type 2 diabetes, and at least 5 of
  those overweight (BMI 25 - 30 kg/m2, proposed gt
  23 kg/m2 in Asians )
• central obesity (routine anthropometric
  measurements)waist gt 85 cm women, gt 97 cm men
• waist hipgt 0.85 women, gt 0.90 men

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Prevalence

• the estimated prevalence of hepatic steatosis
  (nonalcoholic fatty liver disease) in the general
  population is 20
• prevalence of NASH is not well-defined, it is
  reported world-wide and is detected in 1.2 to 9
  of patients who have liver biopsy
• the prevalence of NASH in obese is 20 and there
  is 2-3 fold increase in diabetes (40 of pts with
  NASH have diabetes, additional 25 give the
  family history of NIDDM)
• ultrasonographic studies on normal population in
  US show a prevalence of 25 for NAFLD (imaging
  cannot distinguish between steatosis and NASH)
• data from patients who have had liver biopsies
  show that alcoholic hepatitis is still 10 to 15
  times more common than NASH.

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Importance of NAFLD and NASH

• NAFLD is common disorder, mild, non-progressive
• it overlaps with steatosis
• NAFLD became most common liver disease in western
  economies, 2-3 times more common than HBV, HCV
  and ALD (alcoholic liver disease)
• there is rising prevalence in Asia-Pacific region
• NASH became widely accepted as important cause of
  liver disease (liver failure)
• NASH can develop CC, end-stage liver disease

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Patient profile

• obese middle-aged women
• diabetes mellitus
• hypercholesterolemia, or hypertriglyceridemia
• asymptomatic hepatomegaly
• 2-4-fold elevation of serum aminotransferase
  levels (unexplained)
• other LFTs results are usually normal

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Laboratory Evaluation - ALT

• ALT is the most cost-effective screening test for
  metabolic or drug-induced liver injury
• ALT is useful for detecting acute and chronic
  hepatic injury, not related to severity of acute
  hepatic injury and only weakly related to
  severity of chronic hepatic injury
• the definition of chronic hepatic injury by
  increased ALT is widely accepted - Increased ALT
  (without another explanation) on more than one
  occasion over a period of 6 months
• if increased ALT is found on routine testing,
  this should be confirmed by repeat testing before
  further evaluation
• ALT may be normal in patients with cirrhosis,
  whereas AST remains increased
• AST should also be measured with history of
  alcohol abuse

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Laboratory evaluation - AST

• AST lt 10 times normal is non-specific and may
  occur with any form of liver injury
• AST usuallylt50 IU/L in fatty liver
• lt 100 IU/L in alcoholic cirrhosis
• lt 150 IU/L in alcoholic hepatitis
• lt 200 IU/L in 65 of patients with cirrhosis
• lt 200 IU/L in 50 with meta to liver, leukemia
• AST is normal in 25, ALT is normal in 50 cases
  of alcoholic cirrhosis

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Laboratory Evaluation ASTALT

• ASTALT ratio is a useful index for
  distinguishing NASH from alcoholic liver disease
• typically lt1 in NASH,with progression to
  cirrhosis the ratio often increases to gt1
• a ratio of gt or 2 is strongly suggestive of
  alcoholic liver disease (alcoholic hepatitis and
  cirrhosis)
• ASTALTlt1 occurs in 70 of NASH patients compared
  with 26 of patients with post-necrotic
  cirrhosis, 8 with chronic hepatitis, 4 with
  viral hepatitis, and none with obstructive
  jaundice

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Laboratory evaluation - ASH

• increased GGT and MCVgt 100 together or separately
  in occult alcoholism
• increased AST (lt300 IU/L) with normal ALT
• AST ALT gt1 and ASTlt 300 IU/L identifies 90 of
  people with alcoholic liver disease
• ALP normal or moderately increased in 20-50 of
  cases (not useful test)
• changes last gt 6 wks after abstaining from
  alcohol
• advanced disease increased PT - indicator of
  poor prognosis
• increased WBC, anaemia
• PT gt5 s above reference, bilirubin gt428 µmol/L
  (gt25 mg/dL), or albumin decreased lt25 g/L (2.5
  g/dL) in a patient gt55 years of age predicts 90
  likelihood of death .

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Clinical diagnosis of NASH

• convincing evidence of negligible alcohol
  consumption
• mild elevation of ALT, GGTP
• anthropometric measurements
• determination of insulin resistance (fasting
  serum insuline and glucose levels, c-peptide)
• serum lipids raised TG, low HDL-C
• increased echogenicity on US (fatty liver)
• absence of serologic evidence of previous
  infection with the hepatitis B or C virus
• a liver biopsy is recommended

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Diagnosis before biopsy

• NASH
• predictive value of a diagnosis of NAFLD before
  biopsy is only 56 for NASH

• ASH
• predictive value of a diagnosis for alcoholic
  liver disease is 86

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Predictors of the degree of fibrosis

• NASH
• age( gt 45-50 yrs), sex (F), obesity, and diabetes
  mellitus hyperlipidemia (triglicerydemia)
• grade of Perls stain (Liver iron overload)

• ASH
• age, sex, BMI, Perls grade, and blood glucose
  level

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Chronic Hepatic Injury

• NASH
• 8 to 20 of patients with NASH progress to
  cirrhosis
• liver-related deaths occur in 8 of these
  patients, over a 10-year period

• ASH
• 38 to 50 of patients with alcoholic hepatitis
  progress to cirrhosis
• at high risk of accelerated alcoholic liver
  injury are women, obese and those with
  hepatitis C

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Life expectancy

• NASH
• 5-year survival 67
• 10-year survival 59
• patients with NASH have lower life expectancy
  than age- and sex-matched controls from the
  normal population

• ASH
• 5-year survival 38
• 10-year survival 15

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Clinical Course

• NASH can progress to liver fibrosis, cirrhosis
  and chronic hepatic failure, eventually to the
  need for a liver transplantation
• up to 50 of NASH patients develop liver fibrosis
  15 develop cirrhosis, 3 may progress to
  terminal liver failure, requiring liver
  transplantation (the treatment of choice for
  end-stage liver disease secondary to NASH)
• cryptogenic liver cirrhosis accounts for 10 of
  liver cirrhosis and is associated with NASH
  (obesity, NIDDM)
• NASH plays also a role in the development of HCC

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Alcohol consumption
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Excessive alcohol consumption

• routinely used markers gamma-glutamyltransferase,
  mean corpuscular volume, levels of AST and ALT -
  detect alcohol-induced liver impairment
• new markers carbohydrate deficient transferrin
  (CDT) and WBAA whole-blood-associated
  acetaldehyde assay (HAA), EDAC (early detection
  of alcohol consumption test)
• EDAC as screening tool for detection heavy
  alcohol abuse, CDT as confirmatory test (FDA
  approved)

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Alcohol screen for insurance
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Alcohol screen for insurance
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NASH/ASH screen for insurance in CEEC
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Questions to be answered before ordering a new
test. Brackenridge decalogue

• 1. Is the test cost-effective?
• 2. Is it safe?
• 3. Is it convenient for screening?
• 4. Is it accepted by the medical community?
• 5. What are the sensitivity, specificity and
  predictive value of the test?
• 6. Can the test be done by the reference
  laboratories used by insurance industry
  (ex.Eastern Europe)?
• 7. Does the test deal with the impairment of
  significant morbidity / mortality?
• 8. Does the impairment tested occur frequently
  enough within the insured population (country,
  continent) to justify the demand for test?
• 9. Does the test improve the equity of the
  underwriting process by more accurately assigning
  individuals to appropriate risk classes?
• 10. Does the test enhance value to the consumer
  by keeping insurance costs low and product
  availability high for the great majority of
  insurance applicants?