gastroenterology and hepatology - abnormal lfts
TRANSCRIPT
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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. Liver biopsy: inflammation.
Response to steroids.
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Alpha-1 Antitrypsin
Deficiency A1AT level.
A1AT phenotype. Liver biopsy:PAS positive- diastase
resistant hepatocellulargranules.
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Celiac Disease
Affects 1/100 people.
A cause of abnormal LFTs.
A cause of liver failure.
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Wilsons Disease
Age < 55.
Hemolytic anemia, movementdisorder, coma.
Diagnosis: low ceruloplasmin,high 24 h urine copper, KFrings, liver biopsy.
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Hepatocanalicular
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Hepatocanalicular
Mixed pattern: elevated transaminasesand alk phos.
Medications: ASA, NSAIDs,antibiotics.
Alcohol
Overlap syndrome: PBC + AI-CAH
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Canalicular/Cholestatic
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Canalicular/Cholestatic
Elevated alk phos and bilirubin
Sepsis
Drug-induced cholestasis
Post-operative jaundice Genetic disorders: Gilberts syndrome
TPN
Primary Biliary Cirrhosis (PBC) Primary Sclerosing Cholangitis (PSC)
Biliary obstruction
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60 yo man with history of alcohol abuse andhepatitis C sustained multiple trauma in
MVA requiring exploratory laparotomy.
Received multiple units of PRBCs. Required
intubation/PEEP, antibiotics for pneumonia,
blood cultures positive, on TPN.
You are consulted for evaluation of abnormalLFTs. Bilirubin 26, alk phos 350, ALT 150,
INR 1.6
CASE #1
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Multifactorial
Postoperative jaundice Sepsis
Medications
TPN
Increased pigment load:hemolysis of transfused cells,
resorption of hematomas.
Ventilator/PEEP
Underlying liver disease
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Postoperative Jaundice
25-75% of pts develop abnl LFTs
post-op. 47% of cirrhotics become jaundiced.
History:type of surgery, blood products,
hypoxia, hemodynamics, anesthetic, meds, TPN,rule-out infection.
Postoperative Jaundice
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Isolated unconjugated hyperbilirubinemia.
Hemolytic disorders: G-6PD def,SS dz, thallasemias, autoimmune, meds,
infection, DIC. Hemolysis of transfusedPRBCs.
Resorption of hematomas. Gilberts syndrome.
Postoperative Jaundice
Postoperative Jaundice
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Hemolysis Increased reticulocytes
Unconjugatedhyperbilirubinemia (bili < 5 mg/dl)
Increased AST and LDH
Decreased haptoglobin Schistocytes
Normal alk phos and ALT
Postoperative Jaundice
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Sepsisand cholestasis.
Endotoxins (LPS) induceinflammatory cytokines.
Impaired transport of bile acidsand bilirubin; decreased bile flow.
100 consecutive septic pts:54% elevated bili (34% > 2), worse with liver dz,preceded bacteremia in 1/3 by 1 to 9 days, 61%mortality, 100% mortality with persistent jaundice.
Postoperative Jaundice
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TPN 2 weeks fatty livermoderate
increases in ALT and alk phos. > 3 weeks cholestasis.
Treatment: avoid excess non-protein
calories, cycle TPN (10-12 hrs), add lipids,r/o acalculous cholecystitis.
Postoperative Jaundice
Postoperative Jaundice
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Acalculous Cholecystitis
Risks:male, major surgery, trauma, burns, long-termTPN, mech vent with PEEP, narcotics, renal failure.
Fever, pain, leukocytosis, non-specific
LFTs. CT and US:pericholecystic fluid, thickened
wall. (HIDA, too many false +/-.)
Treatment: cholecystectomy, -cystostomy. Mortality: 70%.
Postoperative Jaundice
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30 yo male GI fellow was told by hisattending that he is jaundiced, especially
prominent on the day after weekend
call. Complains of fatigue and
irritability. Drinks an occasional
margarita.
Physical exam with mild icterus.Bili 3.9 (all indirect), LFTs o/w normal.
Case #2
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Gilberts Syndrome
Decreased UDP glucuronyl
transferase levels. Unconjugated hyperbilirubinemia.
Total bilirubin < 4 mg/dl.
Rule-out hemolysis.
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51 yo woman with pruritus, fatigue and
jaundice, worsening over several years.
Past history of hypothyroidism, sicca
syndrome and hypercholesterolemia.
PE: jaundice, splenomegaly, xanthoma,
bruising.
Lab: bili 10.5, alk phos 650, ALT 95,
INR 2.5, plts 65k.
Case #3
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AMA + 1/640
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Primary Biliary Cirrhosis
(PBC)
A chronic autoimmune hepatobiliarydisease resulting from T cell-mediatedapoptotic destruction of biliaryepithelial cells lining interlobular to
septal caliber intrahepatic bile ducts.
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PBC: Florid Duct Sign
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PBC:Clinical Features
Female 82%.
Age at diagnosis: 51 (middle age).
AMA + in 92-95%. Symptoms: fatigue, pruritus, arthralgias.
Signs: jaundice, hypothyroid, sicca, Raynauds.
Prognosis: (Mayo Risk Score) age, bili, alb, PT,edema.
A progressive disease ending in liver failure.
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24 yo man with chronic bloody
diarrhea. Also c/o pruritus.
Lab: bili 8.5, alk phos 800, INR 2.7,
plts 95 k, Ca++ 6.5
Case #4
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Primary Sclerosing Cholangitis(PSC)
A chronic cholestatic liver disease ofunknown pathogenesis that is stronglyassociated with chronic ulcerative colitis.
Characterized by progressive
destruction of bile ducts, resulting in thedevelopment of biliary cirrhosis.
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PSC:Clinical Features
Prevalence 6-8 cases/100 k
M/F = 3/1
Presents ~ age 20-30
80% of PSC patients have IBD.
4% of IBD patients have PSC. Median survival ~ 12 yrs.
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PSC:Symptoms
Pruritus
Jaundice
Abdominal pain Fatigue
Complications of cirrhosis and portal HTN.
Bacterial cholangitis Cholangiocarcinoma: lifetime prevalence 10-30%.
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PSC: Diagnosis
Clinical, biochemical, histologic findings.
ERCP multifocal strictures and dilationsinvolving intra- and extrahepatic ducts.
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Liver Imaging
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Imaging US and CT: useful for fatty liver, r/o dilated
ducts, screening for hepatoma, patency ofhepatic and portal veins, cholecystitis,pancreatic mass.
MR/MRCP: useful for ductal disease,choledocholithiasis, iron overload, hepatoma vshemangioma.
ERCP/EUS: rule out PSC, PBC,
cholangiocarcinoma, pancreatic neoplasm,choledocholithiasis, ampullary neoplasm,adenopathy.
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Liver Biopsy
Grade and stage viral hepatitis. Unknown cause of liver disease
(rule out fatty liver, granulomatoushepatitis).
Rule outAI-CAHIron overloadWilsonsA1AT deficiency
Cirrhosis?
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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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Staging Liver Disease
Severity of Liver Disease:
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Severity of Liver Disease:
Child-Turcotte-Pugh Class
Ascites None Slight Mod/severe
Encephalopathy None Slight/mod Mod/severe
Bilirubin 3.0
Albumin >3.5 2.8-3.5 6
Parameter 1 2 3
Total numerical score
5-6
7-9
10-15
Child-Turcotte-Pugh class
C
B
A
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Model for End-Stage LiverDisease (MELD)
Mathematical survival model created fromdata on patients undergoing TIPS
MELD score estimates risk of 3-monthmortality
Uses 3 laboratory values
- Serum total bilirubin- Serum creatinine
- INR
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Calculating MELD Scores
The hard way6.4 + 9.8 x log (INR) + 11.2 x log (Cr) +
3.8 x log (Bilirubin)
The easy way
www.unos.org/resources/
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Ascites and Prognosis
Ascites occurs in of cirrhoticpatients within 10 yrs.
50% 2 year mortality.
75% 1 year mortality withrefractory ascites.
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SBP Treatment
IV albumin: 1.5 g/kg on day 1 and 1
g/kg on day 3. Reduced risk of renalfailure and improved survival.
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Hepatorenal Syndrome
HRS: functional renal failure in the
setting of cirrhosis and in the absence
of intrinsic renal disease.
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HRS: Treatment Midodrine: an alpha agonist that improves
systemic blood pressure, thereby improvingrenal perfusion.
Octreotide: antagonizes the action ofvarious splanchnic vasodilators.
Albumin: increases circulatory volume.
Combined: improved systemic hemodynamics improved renal circulation.
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HRS: MOA
Midodrine, octreotide and albumin (5pts) vs dopamine and albumin (8 pts)for 20 days.
Improvement in renal function with noside-effects in all 5 on MOA (1/8 ondopamine improved).
Angeli, et al. Reversal of type 1 hepatorenal
syndrome with the administration of midodrine
and octreotide. Hepatology, 19:1690, 1999.
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HRS:midodrine, octreotide, albumin.
14 ascitic cirrhotic pts with type 1 HRS.
Midodrine 2.5 mg/d, octreotide 25 mg/h and albumin50 g/d for 14 days reversed HRS in 10 of 14 pts.
Subsequent TIPS in 5 pts maintained normal renalfunction at 1 y.
2 responders transplanted.
Wong, et al. Midodrine, octreotide, albumin and
TIPS in selected patients with cirrhosis and type 1
hepatorenal syndrome. Hepatology 40:55, 2004.
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