Gastroenterology and Hepatology - Cholestatic Syndromes

8/22/2019 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.



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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



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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.



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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%.



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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

Gastroenterology and Hepatology - Cholestatic Syndromes

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