Gastroenterology and Hepatology - Cholestatic Syndromes
Transcript of Gastroenterology and Hepatology - Cholestatic Syndromes
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Cholestatic SyndromesJeffrey C. Dunkelberg, MD, PhD
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Goals:
Know the treatable causes of liver disease.
Understand the 3 patterns of abnormal LFTs.
Know the differential diagnosis of cholestasis.
Be able to select appropriate diagnostic tests.
Know treatment options, treatment limitations.
Cholestasis
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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
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Hepatocanalicular
Mixed pattern: elevated transaminases and alk phos.
Medications: ASA, NSAIDs, antibiotics.
Alcohol
Overlap syndrome: PBC + AI-CAH
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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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Cholestasis
Decreased bile flow resulting fromreduced biliary secretion or from
obstruction of the biliary tree.
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Cholestasis: Labs
Alkaline phosphatase > 3-5 x normal.
Elevated GGT and 5 nucleotidase.
Transaminases < 3 x normal.
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Acute
Cholestasis:Clinical manifestations
Jaundice
Pruritus
Anorexia, malaise,
fatigue
Abdominal pain
Hypersensitivity:fever, rash,
eosinophilia
Weight loss
Hypercholesterolemia
xanthoma Melanoderma
Hepatomegaly
Splenomegaly
Portal hypertension
Fat-soluble vitaminmalabsorption
Chronic
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Cholestasis:
Fat-soluble vitamin malabsorption.
Vitamins D, A, K, E.
Calcium deficiency. Hepatic bone disease
osteoarthropathy, osteomalacia, osteoporosis
Bruising, coagulopathy.
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54 yo woman presents with jaundice, fatigue,
anorexia.
No EtOH. No co-morbid medical problems.
PE: jaundice.
Bili 14, AP 400, ALT 600, INR normal. Lab screen
negative for cause.
US normal.
Liver biopsy: cholestasis, bile casts.
CASE #1
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IBUPROFEN stopped and LFTs normalized
within 6 weeks.
Syndrome recurred with accidental
rechallenge.
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Cholestasis:Drug Hepatotoxicity
Sulfonamides, PCN, TCN, fluconazole,
phenytoin, anti-emetics, NSAIDs.
Occurs within 2 weeks12 months of
exposure.
Fever, pruritus, skin rash, arthralgias,
eosinophilia.
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Clinical features:
An acute illness; resolves with drug
discontinuation.
Hypersensitivity: fever, rash, eosinophilia.
Management:
Supportive. Stop drug. Ursodiol for prolonged syndrome.
Rifampin or naloxone for pruritus.
Drug-induced cholestasis
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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. Requiredintubation/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 #2
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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.
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Isolated unconjugated hyperbilirubinemia.
Hemolytic disorders: G-6PD def, SS dz,thallasemias, autoimmune, meds, infection, DIC.
Hemolysis of transfused PRBCs.
Resorption of hematomas. Gilberts syndrome.
Postoperative Jaundice
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Hemolysis Increased reticulocytes
Unconjugated hyperbilirubinemia(bili < 5 mg/dl)
Increased AST and LDH
Decreased haptoglobin
Schistocytes
Normal alk phos and ALT
Postoperative Jaundice
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Halothane Hepatotoxicity
Idiosyncratic
2 weeks post-op
Risks:age > 30, obesity, multiple and shortinterval exposures.
Presentation:jaundice within 2 weeks, rash,arthralgia, tender hepatomegaly.
ALT > 10x normal, hyperbilirubinemia,alk phos < 2x normal, eosinophilia.
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Sepsisand cholestasis.
Endotoxins (LPS) induce inflammatorycytokines.
Impaired transport of bile acids andbilirubin; decreased bile flow.
100 consecutive septic pts:
54% elevated bili (34% > 2), worse with liver dz, precededbacteremia in 1/3 by 1 to 9 days, 61% mortality, 100%mortality with persistent jaundice.
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TPN
2 weeksfatty livermoderate increases
in ALT and alk phos. > 3 weekscholestasis.
Treatment: avoid excess non-protein calories,
cycle TPN (10-12 hrs), add lipids, r/o acalculouscholecystitis.
Postoperative Jaundice
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Acalculous Cholecystitis
Risks:male, major surgery, trauma, burns, long-term TPN,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, cholecystostomy.
Mortality: 70%.
Postoperative Jaundice
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26 yo male Internal Medicine internwho was told by his resident that he is
jaundiced, especially prominent on the
day after call. Complains of fatigueand irritability. Drinks an occasional
margarita.
Physical exam with mild icterus.
Bili 3.9 (all indirect), LFTs o/w normal.
Case #3
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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.
AMA + 1/320.
Case #4
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Primary Biliary Cirrhosis
(PBC)
A chronic autoimmune hepatobiliary
disease resulting from T cell-mediated
apoptotic destruction of biliary
epithelial cells lining interlobular toseptal 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.
PBC Ph i l E Fi di
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PBC: Physical Exam Findings
Xanthomas
Melanodermaand
Raynauds
Telangiectasia
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P i Bi li Ci h i
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Ursodiol for PBC: RCTs
Significant reductions in
biochemical markers ofcholestasis.
Long-term therapy in
prefibrotic histopathologicstages retards development
of fibrosis.
Primary Bi li ary Cirrhosis
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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 #5
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Primary Sclerosing Cholangitis
(PSC)
A chronic cholestatic liver disease of
unknown pathogenesis that is strongly
associated with chronic ulcerative
colitis.
Characterized by progressivedestruction of bile ducts, resulting in
the development 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.
ERCPmultifocal strictures and dilationsinvolving intra- and extrahepatic ducts.
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PSC: Treatment
Nothing, except transplantation, alters course.
Ursodiol +/- biochemical and histologic benefit.
Endoscopic approaches for dominant strictures.
Transplantation
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35 yo HIV-infected man presents with fever,
fatigue and jaundice.
Meds: zalcitobine, ritonavir, TMP-sulfa.
CD 4 count < 200, bilirubin 12, alk phos 1450,
ALT 150, bicarb 12, lactate 4.5.
Case #6
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Cholestasis in HIV-infected
patients.
Liver disease in HIV: a new morbidity. Cholestasis in up to 55% of patients.
Alk phos > 1000 IU/ml in 17%.
Overt jaundice in 7 %.
HIV and Cholestasis
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HAART: Drug-induced
cholestasis.
Hepatotoxicity in 6-10%.
Nucleoside RTIs: mitochondrial toxicity.zalcitobine > stavudine > didanosine
Lactic acidosis
LDH, amylase, lipase elevations
Non-nucleoside RTIs (nevirapine):immune-mediated adverse rxns
HIV and Cholestasis
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HIV and Cholestasis
Other meds:protease inhibitors, macrolides,TMP-sulfa, pentamidine, antifungals, anti-TBagents.
Infections: CD 4 counts < 200.
Rochalimaea (bacillary angiomatosis)
MAI
Fungalcryptococcal, histoplasma Neoplasms:Kaposis sarcoma, lymphoma.
HIV-related biliary tract disease.
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Goals:
Know the treatable causes of liver disease.
Understand the 3 patterns of abnormal LFTs.
Know the differential diagnosis of cholestasis.
Be able to select appropriate diagnostic tests.
Know treatment options, treatment limitations.
Cholestasis