You Ordered It...Now What?
Evaluation of Abnormal Liver Tests
Barry Schlansky, MD MPH
Assistant Professor of Medicine Division of Gastroenterology & Hepatology
Oregon Health and Science University
Overview of Liver Tests
The ‘Liver Panel’:
• AST, ALT, alk phos, GGT, total bilirubin, albumin, sometimes GGT and direct bilirubin
The True Liver Function Tests:
• Albumin, bilirubin, prothrombin time/INR • Others (clotting factors, lactate, cholesterol)
Ammonia is a poor test of liver function and poorly correlates with hepatic encephalopathy
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Patterns of Abnormal Liver tests
Hepatocellular
AST/ALT >>> bili, alk phos
Cholestatic
Bili, alk phos >>> AST, ALT
Mixed
Bili, alk phos ~ AST, ALT Viral hepatitis (A, B, C, D, E) Obstruction (gallstones, tumors) Alcoholic hepatitis Nonalcoholic steatohepatitis Primary biliary cholangitis Vascular / congestion Autoimmune hepatitis Primary sclerosing cholangitis Drug induced liver injury Hemochromatosis Infiltration (cancer, sarcoid, TB)
Wilson’s disease Vascular / congestion Alpha-1-antitrypsin deficiency Drug induced liver injury Celiac disease
Vascular / congestion Drug induced liver injury
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Liver Macro-Anatomy
Three Lobes (left, right, and caudate) Dual Blood Supply:
• Portal vein – 75% blood, 50% O2
• Hepatic artery – 25% blood, 50% O2
The portal vein drains the esophagus, stomach, spleen, and intestines into the liver
Liver Micro-Anatomy
Lobule= anatomic unit of the liver • Six portal triads surrounding cords of
hepatocytes with a central vein
Portal triad = portal venule, hepatic arteriole, and bile ductule
• Arterial and venous blood mix in the hepatic sinusoids, flows to central vein Separate system of bile canaliculi drain bile in the opposite direction to the bile ductule
AST and ALT
ASpartate and ALanine aminoTransferase• AKA SGOTand SGPT
Intracellular hepatocyte enzymes involved in gluconeogenesis • Leak out in times of injury, measured in the serum • AST also in myocardium, skeletal muscle, brain, stomach,
kidney, pancreas, spleen, lung, and erythrocytes (90% of serum AST is from the liver)
• ALT ispredominatelyhepatic (minute amounts in kidney and muscle) (~100% of serum ALT is from the liver) Commonly abnormal – a 2002 study found elevated ALT levels in 8.9% of the U.S. population
• Likely higher with stricter ULN (<30 in men, <20 in women)
Alkaline Phosphatase
Enzyme in hepatocyte membrane lining the bile canaliculi
• Localized in liver > bone > intestine; also produced by the placenta • Fluctuates with age:
• A liver origin for an elevated alk phos can be confirmed by testing the GGT or 5’-nucleotidase, or it can be fractionated • Isolated liver alk phos elevations can occur with infiltrative
liver diseases (lymphoma, sarcoidosis, TB), PBC/PSC, and certain drugs (phenytoin)
50 100 150 200 250 300 350 400 5 15 25 35 45 55 65 75 85 6
Bilirubin
• Most (~80%) bilirubin is a product of heme degradation
ÆUnconjugated (indirect) bilirubinreleased into the blood bound to albumin
ÆHepatocyte ER conjugates bilirubin to its direct form ÆDirect bilirubin excreted into the bile (rate-limiting)
• Elevated bilirubin may reflect over-production(hemolysis – rarely >5 mg/dL), impaired conjugation (Gilbert’s syndrome – rarely >3 mg/dL), impaired secretionby hepatocytes (liver injury/failure), or blockage of bile flow(biliary obstruction)
• Over-production and impaired conjugation cause predominately indirect hyperbilirubinemia
• Impaired secretion or blockage cause mixedor direct
hyperbilirubinemia 7
The True Liver Function Tests
Albumin• Plasma protein synthesized by the liver (t1/2=14-21 days) • Levels <3.5 mg/dL suggest chronic/advanced liver disease • Non-specific– Production inhibited by inflammation, infection,
protein malnutrition, and alcohol abuse Prothrombin time/INR
• Liver synthesizes extrinsic pathway clotting factors (I, II, V, VII, IX, X, XII, and XIII) and some vWF
• Many are vitamin K-dependent and are reduced in both liver disease and vitamin K deficiency
• INR is one of the most sensitive measures of acute liver failure (with presence of encephalopathy)
• Does notrepresent bleeding risk in liver disease – ‘auto-anticoagulation’ is not a real thing 8
Evaluation of Abnormal Liver Tests
1. First, repeat the test!• Many things cause a one-time elevation of liver tests • Except for viral hepatitis serologies in high-risk patients,
mild liver test elevations should be monitored for 3-6 months before a full lab work-up for etiology is performed
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Evaluation of Abnormal Liver Tests
1. First, repeat the test!2. How abnormal are the liver tests?
• Normal = 2 SD above and below the mean in a young, healthy population
• Thus, 2.5% of normal, healthy people will have an abnormal test
• Do they have a condition where an high test is ‘normal’? (alk phos in pregnancy, AST in a marathon runner, INR in a coumadin user)
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Evaluation of Abnormal Liver Tests
1. First, repeat the test!2. How abnormal are the liver tests?
3. Detailed history
• Duration of elevation, symptoms (pruritus, fatigue, pain, arthralgias/myalgias, fever, weight loss, urine/stool changes)
• Medications (including OTC/supplements, dose changes, duration of exposure)
• PMH
• Personal or family history of autoimmune disease
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Evaluation of Abnormal Liver Tests
1. First, repeat the test!2. How abnormal are the liver tests?
3. Detailed history
• Social history is crucial!
– How much do you drink? (be specific!) – Recent travel or immigrant?
– Prior blood transfusions before 1991, tattoos, hemodialysis?
– Healthcare worker with prior needlestick? – Prior injection or intranasal drug use, even once? – Mushroom ingestion?
– High-risk sexual behavior? (MSM, multiple partners,
Evaluation of Abnormal Liver Tests
1. First, repeat the test!2. How abnormal are the liver tests? 3. Detailed history
4. Examination
• Stigmata of chronic liver disease (Spider
telangiectasias, firm liver edge, splenomegaly, ascites, edema, caput medusae, temporal wasting, palmar erythema, jaundice/icterus, asterixis)
• Most of the time, history + exam will provide the likely cause of the abnormal liver tests
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Evaluation of Abnormal Liver Tests
1. First, repeat the test!2. How abnormal are the liver tests? 3. Detailed history
4. Examination
5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements
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Evaluation of Abnormal Liver Tests
Elevated AST/ALT
1. First, repeat the test!2. How abnormal are the liver tests? 3. Detailed history
4. Examination
5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements
6. Elevated AST/ALT Initial Work-Up:
• HCV-Ab (reflex RNA if +), HBsAg, HBcAb-IgM/IgG, HAV-IgM/IgG, HBsAb, ferritin and % transferrin saturationÆif negative, monitor for 3-6 months
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Evaluation of Abnormal Liver Tests
Elevated AST/ALT
1. First, repeat the test!2. How abnormal are the liver tests? 3. Detailed history
4. Examination
5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements
6. Elevated AST/ALT Initial Work-Up
• Initial work-up negative and AST/ALT remain elevatedÆRUQ ultrasound with Dopplers, ANA, anti-smooth muscle, SPEP, D1AT level, anti-TTG, TSH, ceruloplasmin (if age <50)
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Evaluation of Abnormal Liver Tests
Elevated Bilirubin or Alk Phos
1. First, repeat the test!2. How abnormal are the liver tests? 3. Detailed history
4. Examination
5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements
6. Elevated Bilirubin / Alk Phos Initial Work-Up:CMP, CBC, INR, and RUQ ultrasound with Dopplers
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Evaluation of Abnormal Liver Tests
Elevated Bilirubin or Alk Phos
1. First, repeat the test!2. How abnormal are the liver tests? 3. Detailed history
4. Examination
5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements
6. Elevated Bilirubin / Alk Phos Initial Work-Up:CMP, CBC, INR, and RUQ ultrasound with Dopplers
• Evidence of biliary obstruction: CT or MRI-MRCP, ERCP, EUS-FNA, tumor markers if mass present • No evidence of biliary obstruction:AMA, IgG4, CT or
MRI-MRCP Æpossible ERCP or liver biopsy
When to Worry!
1. Severe Hepatocellular Injury: AST/ALT >15x ULN (~400) 1. Severe Drug-Induced Liver Injury: AST/ALT >3x and
bilirubin >2x ULN with normal alk phos
• Hy’s Law– predicts liver failure with a 10% case fatality rate 1. Hepatic Synthetic Dysfunction: Acutely elevated liver
tests (AST/ALT, bili, alk phos) with associated increases in the INR (>1.5) or development of hepatic encephalopathy in a patient without known cirrhosis
• Acute Liver Failure –warrants urgent hospitalization
1. Acute Cholangitis:Elevated bilirubin and alk phos with associated RUQ abdominal pain and fever (Charcot’s triad)
• Reynold’s pentad= Charcot’s + shock + confusion Æ50% mortality
Cases
Case #1
• 48 year-old man with abnormal liver tests at annual physical • No significant past medical history
• No medications
• Tried IV drugs “one time in college” • Normal physical exam
• Labs – Normal BMP and CBC
• AST 62, ALT 88, Alk Phos 75, total bili 0.7, INR 1.0, albumin 4.1
• Normal abdominal ultrasound
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Case #1
• 48 year-old man with abnormal liver tests at annual physical • No significant past medical history
• No medications
• Tried IV drugs “one time in college” • Normal physical exam
• Labs – Normal BMP and CBC
• AST 62, ALT 88, Alk Phos 75, total bili 0.7, INR 1.0, albumin 4.1
• Normal abdominal ultrasound • HCV-Ab+
• What now?
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Case #1
• 48 year-old man with abnormal liver tests at annual physical • No significant past medical history
• No medications
• Tried IV drugs “one time in college” • Normal physical exam
• Labs – Normal BMP and CBC
• AST 62, ALT 88, Alk Phos 75, total bili 0.7, INR 1.0, albumin 4.1
• Normal abdominal ultrasound • HCV-Ab+
• What now?
• HCV RNA, HCV genotype, HBsAg, HBcAb, HBsAb, HIV
• Hepatitis A and B vaccinations, Hepatology referral 23
Case #1: Hepatitis C
• HCV-Ab positivity indicates active infection or prior exposure with immune clearance (~25%)
• False positives with rheumatologic disease • False negatives in immunosuppressed patients
• HCV-Ab seroconverts ~8-16 weeks after exposure (can test HCV RNA if HCV-Ab negative with acute liver test elevation) • HCV RNA detectable ~2 weeks after exposure, level does
not correlated with severity of liver disease
Case #2
• 45 year-old male Somalian immigrant with abnormal liver tests at routine physical
• PMH: hyperlipidemia
• No medications or prior alcohol or drug use • Born in Somalia, emigrated to U.S. in 1990
• Father died from liver cancer but otherwise no known history of viral hepatitis
• Normal physical exam • Labs – Normal BMP and CBC
• AST 50, ALT 60, Alk Phos 70, total bili 0.5, INR 0.8, albumin 3.9
• Abdominal ultrasound – 3-cm liver mass
• What now? 25
Case #2
• HBsAg positive • HBsAb negative
• Total HBcAb positive (HBcAb-IgM negative)
• Further testing: HBV DNA 100 million IU/mL, HBeAg+, HBeAb-, AFP 954 liver protocol CT with 3-cm right lobe hepatocellular carcinoma
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Case #2: Hepatitis B
• HBsAg positive • HBsAb negative
• Total HBcAb positive (HBcAb-IgM negative)
• Further testing: HBV DNA 100 million IU/mL, HBeAg+, HBeAb-, AFP 954 liver protocol CT with 3-cm hepatocellular carcinoma
• Diagnosis – Chronic Hepatitis B (likely vertically transmitted)
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Global Distribution of Hepatitis B
• 350 million chronic carriers worldwide
• Ninth leading cause of death worldwide
• Nearly 75% of HBV chronic carriers are Asian
• High risk of liver cancer in Sub-Saharan African patients
HBsAg Prevalence (%)
tt8: High
2-7: Intermediate
<2: Low 28
Interpretation of Hepatitis B Serology
HBsAg HBsAb HBcAb HBV DNA Interpretation
+ - + (IgM) + Acute Hepatitis B Infection + - + (IgG) + Chronic Hepatitis B Infection - + - - Vaccinated for Hepatitis B - +/- + - Past Exposure to Hepatitis B
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Interpretation of Hepatitis B Serology
HBsAg HBsAb HBcAb HBV DNA Interpretation
+ - + (IgM) + Acute Hepatitis B Infection + - + (IgG) + Chronic Hepatitis B Infection - + - - Vaccinated for Hepatitis B - +/- + - Past Exposure to Hepatitis B • HBeAg and HBeAb are only applicable to patients with chronic
hepatitis B infection
• Chronic activeinfection = elevated ALT and HBV DNA, needs antiviral treatment
• Chronic inactive (carriers)= normal ALT and low level HBV DNA, needs active surveillance for HBV flares (conversion to active) • HBeAg can be negative in active infection (precore mutation), treated similarly to HBeAg+ chronic active hepatitis B 30
Case #3
• 19 year-old healthy female college student with several days of fatigue, jaundice, and mild pruritus
• No alcohol or drug use, no medications • No high-risk behavior, sick contacts, or travel • Recent ear infection treated with Augmentin • Exam – icterus, jaundice, otherwise normal • Labs – Normal BMP and CBC
• AST 180, ALT 290, Alk Phos 248, total bili 8.5, INR 0.9, albumin 4.4 • Negative viral serologies
• Abdominal ultrasound normal • What is the diagnosis?
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Case #3: Drug-Induced Liver Injury
• Liver tests normalized over 8 weeks after stopping Augmentin • #1 cause of DILI in the U.S. is acetaminophen• As little as 2-3 gm/d can cause toxicity with alcohol / fasting
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Case #3: Drug-Induced Liver Injury
• Liver tests normalized over 8 weeks after stopping Augmentin • #1 cause of DILI in the U.S. is acetaminophen• As little as 2-3 gm/d can cause toxicity with alcohol / fasting
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Top Ten Prescription Causes of DILI
(NIH DILI Network)
Rank Agent Percent
1 Amoxicillin/clavulanic acid 12% 2 Isoniazid 7% 3 Nitrofurantoin 6% 4 TMP-SMX 4% 5 Minocycline 4% 6 Cefazolin 3% 7 Azithromycin 2% 8 Ciprofloxacin 2% 9 Diclofenac 2% 10 Levofloxacin 2%
All of the top 20 drugs for DILI were approved before 2000 34
Case #4
• 56 year-old woman with several months of fatigue, myalgias • No alcohol or drug use, no medications
• PMH – type 1 diabetes, Hashimoto’s thyroiditis • Exam – scleral icterus, otherwise normal • Labs – Normal BMP and CBC
• AST 350, ALT 400, alk phos 205, total bili 2.5, INR 1.0, albumin 3.4 • Negative viral serologies
• Abdominal ultrasound with mild hepatomegaly
• What is the leading diagnosis? What additional labs?
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Case #4
• ANA 1:640, ASMA 1:380, SPEP with elevated IgG level • Diagnosis – Autoimmune Hepatitis(probable)
Case #4: Autoimmune Hepatitis
• ANA 1:640, ASMA 1:380, SPEP with elevated IgG level • Diagnosis – Autoimmune Hepatitis(probable)• Biopsy required – interface hepatitis with plasma cells • Middle-aged woman, non-drinker, without viral hepatitis • Symptoms – Fatigue, arthralgias/myalgias, jaundice • Often history of other autoimmune disease
• Increased AST/ALT (can be >1,000), often elevated bilirubin, elevated ANA, ASMA (F-actin), and IgG • Prompt response to steroids, followed by long-term
steroid-sparing immune suppression (azathioprine) 37
Case #5
• 60 year-old obese man with new-onset diabetes found to have elevated liver tests
• PMH: DM2, osteoarthritis, HTN • No family history of liver disease • Drinks 4 beers/day, no prior drug use • Exam normal
• Labs – Normal BMP and CBC
• AST 75, ALT 65, alk phos 122, total bili 0.5, INR 0.8, albumin 4.4 • Negative viral serologies
• Normal ultrasound • What other lab testing?
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Case #5
• Ferritin 610, transferrin sat 78% • HFE testing – C282Y homozygote• Diagnosis – Iron Overload Syndrome
• Hemochromatosis vs. Alcohol vs. NASH – or All Three?
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Case #5: Iron Overload
• Ferritin 610, transferrin sat 78%• HFE testing – C282Y homozygote
• Diagnosis – Iron Overload Syndrome
• Hemochromatosis vs. Alcohol vs. NASH – or All Three?
Things to keep in mind:
1. Hemochromatosis = 0.5% of Caucasians (rare other races) 2. Test HFE only if elevated iron tests or in family members 3. C282Y/C282Y penetrance in men = 24-43% (women lower) 4. Hemochromatosis isnotthe most common cause of an
elevated ferritin level in the primary care setting!
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Case #5: Iron Overload
• The Hemochromatosis and Iron Overload Screening (HEIRS)study (2011) tested iron studies and HFE in 44,892 Caucasian primary care patients
• Elevated ferritin in 19% of men (>300), 9% of women (>200) • Most with ferritin <1,000 did not have iron overload HFE genotypes • Inflammation, NASH, and alcohol use are more common causes
Men Women
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Alcoholic Liver Disease
• Occurs in 25% of heavy drinkers• Liberal hepatology definition –21/wk in men, 14/wk women
• Multiple phenotypes:
1. Alcoholic fatty liver (liver tests may be normal) 2. Alcoholic steatohepatitis and cirrhosis (mimics NASH) 3. Alcoholic hepatitis (40% 90-day mortality if severe) • AST > ALT (but always <500)
• Cirrhosis can occur despite normal liver tests
Case #6
• 47 year-old Caucasian woman with several months of pruritus and fatigue
• PMH: osteoporosis, dyslipidemia • No family history of liver disease • No alcohol or drug use history • Exam – skin excoriations • Labs – Normal BMP and CBC
• AST 110, ALT 130, alk phos 450, total bili 1.4, INR 0.9, albumin 4.2 • Negative viral serologies
• Ultrasound with ‘heterogenerous appearing liver’ • What other lab testing?
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Case #6
• AMA+ 1:360, ANA+ 1:80, ASMA-, IgG normal • Diagnosis – Primary Biliary Cholangitis
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Case #6: Primary Biliary Cholangitis
• AMA+ 1:360, ANA+ 1:80, ASMA-, IgG normal • Diagnosis – Primary Biliary Cholangitis• Name changed from Primary Biliary Cirrhosis in 2015 • Autoimmune destruction of intrahepatic bile ducts • AMA 95% specific for diagnosis (ANA+ in 60%) • Biopsy is not required for diagnosis
• Middle-aged women (9:1 F:M)
• Fatigue, pruritus, elevated cholesterol, osteoporosis, xanthomas, fat-soluble vitamin deficiencies (A, D, E, K) • Ursodiol improves liver tests and delays progression to
cirrhosis
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Case #7
• 32 year-old Caucasian man with history of ulcerative colitis presents with fevers, abdominal pain, and jaundice • Exam – jaundice, RUQ TTP
• Labs – Normal BMP and CBC
• AST 120, ALT 130, alk phos 380, total bili 4.4, INR 0.9, albumin 4.2
• Ultrasound with ‘heterogenerous appearing liver’ without biliary dilation
• What test would confirm the diagnosis? • What cancer is the patient at risk for?
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Case #7
• ERCP with diffuse beading of intra- and extrahepatic bile ducts, stones/pus removed with balloon sweeping
• Diagnosis – Acute Cholangitis with underlying Primary
Sclerosing Cholangitis
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Case #7: PSC
• ERCP with diffuse beading of intra- and extrahepatic bile ducts, stones/pus removed with balloon sweeping
• Diagnosis – Acute Cholangitis with underlying Primary
Sclerosing Cholangitis
• MRCP >> ERCP for diagnosis (in absence of cholangitis) • Typically diagnosed in young men, >80% have UC
• PSC + UC is associated with a high colon cancer risk • Colonoscopy at PSC diagnosis and annually thereafter • Most will need transplant within 10 years of diagnosis • Increased risk of cholangiocarcinoma
• Screening – annual MRCP and CA19-9 levels
Case #8
• 68 year-old Hispanic woman with elevated liver tests at routine physical
• PMH – DM2, HTN, dyslipidemia, OSA • Meds – metformin, HCTZ, atorvastatin • FHx of DM2 and CAD, no liver disease • Exam with acanthosis nigricans, morbid obesity • Labs – Normal BMP and CBC
• AST 115, ALT 130, alk phos 80, total bili 0.5, INR 0.7, albumin 4.3
• Ultrasound with increased liver echogenicity • What is the diagnosis?
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Case #8: Nonalcoholic Steatohepatitis
Non-alcoholic fatty liver disease (NAFLD) encompasses:1. Isolated fatty liver – 40% U.S. prevalence, 80% of diabetics, no increased risk of liver mortality/cirrhosis
2. NASH- ~5% U.S. prevalence, associated with risk of cirrhosis
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Case #8: Nonalcoholic Steatohepatitis
Non-alcoholic fatty liver disease (NAFLD) encompasses:1. Isolated fatty liver – 40% U.S. prevalence, 80% of diabetics, no increased risk of liver mortality/cirrhosis
2. NASH- ~5% U.S. prevalence, associated with risk of cirrhosis
• Diagnosis of exclusion, liver biopsy is controversial
• Rising incidenceÆwill eclipse HCV as the #1 indication for liver transplantation and #2 cause of cirrhosis
• Treatment: Weight loss (10%), aerobic exercise, Heart Healthy diet, and excellent control of risk factors (DM, HTN, HLD, OSA, PCOS)
• Statins are OK to use!
• Vitamin E improves histology but controversial (CV and prostate cancer risk), contraindicated with DM or cirrhosis