A Case of Fatal Cholestatic Liver Failure

Senior Clinicopathologic Conference

Andre Cap, MD, PhD

Walter Reed Army Medical Center

History of Present Illness

• 63 y/o white male• Recent radical cystoprostatectomy for poorly

differentiated urothelial carcinoma– 2.5x3 cm bladder mass invading muscle– Negative margins, ureters, LND– Chronic cystitis– T2a N0 Mx

• One month later, developed symptoms c/w acute cholecystitis and underwent laparoscopic cholecystectomy at civilian hospital– Gross pathology reveals bile sludge, no stones, inflammatory

changes consistent with chronic cholecystitis

History of Present Illness (cont.)

• Post-op, LFT’s continued to rise in cholestatic pattern and patient developed painless jaundice and pruritis

• POD#3, patient underwent ERCP– No evidence of retained stone or other obstruction– Stent placed in distal CBD

• POD#5, ERCP repeated due to continued rise in LFT’s– No evidence of obstruction or retained stone– Larger stent placed in CBD and sphincterotomy performed

History of Present Illness (cont.)

• POD#17, HIDA scan performed showing lack of tracer in biliary tree, indicating hepatocellular dysfunction

• CT scan revealed mild intra-hepatic ductal dilatation• Third ERCP revealed patent hepatobiliary tree• Laboratory evaluation of cholestasis unrevealing

– Normal studies: copper, iron, alpha-1 anti-trypsin, ASMA, ANA, AMA, anti LKM, ANCA, Hepatitis A and C

– Hepatitis B core Ab positive (all other Hepatitis B serologies negative, Hep B DNA PCR negative)

• Liver biopsy performed and patient sent to WRAMC for further evaluation

History of Present Illness (cont.)

• Admission medications: protonix, lisinopril, anusol, ursodiol, atarax, dolasetron, nystatin ointment– Previously treated with Augmentin for 10 day course post-

cholecystectomy (unclear how many doses taken)– Previously treated with imipramine for incontinence post-

prostacystectomy, discontinued prior to episode of cholecystitis– Reports 7U PRBC transfusion at civilian hospital, no records

• Patient denied taking herbals, OTC medications, EtOH, tylenol

• Workplace toxin exposure: diesel fuel, other petroleum products

• No family history of liver disease

Other Past Medical History

• Hypertension • Right knee surgery January 2005• Vasectomy • Hernia repair 1968• Tonsillectomy in childhood• NKDA• Prior tobacco use (15 pack-yrs, quit 1981), moderate

alcohol consumption (2-3 beers/week, remote history of heavy EtOH abuse)

Physical Exam / Labs

• Afebrile, BP 113/71, HR 80• Icteric, otherwise unremarkable exam• LFT’s on admission to WRAMC (POD 29):

– Alkaline phosphatase 1249, AST 135, ALT 154, total bilirubin 25.3, conjugated bilirubin 25.2, total protein 7.5, albumin 3.0, INR 1.3

• WBC 14.2, H/H 12.3/35.7, PLT 566• Creatinine 2.2 (baseline 1.7)

Initial Hospital Course

• MRCP performed– No biliary dilatation, complex renal cysts

• ERCP repeated– Beading and minor narrowing of intrahepatic ducts, no CBD

stricture/obstruction

• Exhaustive laboratory evaluation repeated– No etiology for cholestasis identified

• ARF resolved with IV fluids• Liver biopsy repeated

Biopsy Results

• Dr. Zachary Goodman, Chief, Hepatopathology, AFIP

Summary Biopsy Results

• Centrilobular cholestasis, dilated bile canaliculi• Acute cholangitis

– Bile duct injury with PMN infiltration– Ductular proliferation– Mild portal fibrosis

• Inflammatory pseudotumor– Indicative of obstruction and/or ruptured bile duct

Summary Biopsy Results (cont.)

• Biopsies performed at civilian hospital and WRAMC with similar findings– No evidence of malignancy– No evidence of chronic inflammatory changes– No evidence of cirrhosis

• Histopathology consistent with obstruction versus drug effect

Subsequent Hospital Course (6 weeks)

• Worsening cholestatic hepatic failure– Total bilirubin rising to over 50– Coagulopathy developing– Encephalopathy

• Upper GI bleed, multiple episodes– Erosion of CBD stent into duodenum– Duodenal ulcer, jejunal bleeding

• Acute renal failure, requiring dialysis– Thought to be contrast-induced nephropathy, not hepato-renal

syndrome

• Sepsis (VRE)• Death due to sepsis

Subsequent Hospital Course (6 weeks)

0

20

40

60

Total Bili

0

1000

2000

3000

Alk Phos

0

1

2

3

INR

Autopsy Results

• Dr. Zachary Goodman, Chief, Hepatopathology, AFIP

Autopsy Results

• Marked cholestatic liver injury (similar to biopsies)• Centrilobular hepatocellular necrosis, probably due to

hypotension• Granulomata in liver with yeast forms consistent with

Candida (probably acquired in hospital)• Patent extrahepatic biliary tree• Normal pancreas• Evidence of ATN on exam of renal tissue

Differential Diagnosis of Cholestasis

• Biliary obstruction (intra- or extra-hepatic)• Sepsis (inflammatory cascade)• Hepatitis (viral, EtOH)• PBC, PSC• Malignancy (HCC, mets)• Granulomatous disease (infection, sarcoid, drugs –

allopurinol, quinidine, sulfonamides, sulfonylureas)• Pregnancy• Genetic• GVHD• Transplant rejection• Paraneoplastic (RCCA -- Stauffer’s syndrome, NHL, HD,

prostate)• Medication, TPN effect

What can we rule out?

• Biliary obstruction (intra- or extra-hepatic)– ERCP X 4 w/o evidence of obstruction

• Sepsis (inflammatory cascade)– Negative blood cultures until late in clinical course

• Hepatitis (viral, EtOH)– Negative serologies, no EtOH consumption as inpatient

• PBC, PSC– Biopsy results and chronicity not c/w these, negative AMA,

ERCP not c/w PSC• Malignancy (HCC, mets)

– No evidence of hepatic involvement on biopsy, autopsy

What can we rule out?

• Granulomatous disease (infection, sarcoid, drugs – allopurinol, quinidine, sulfonamides, sulfonylureas)– Autopsy reveals few scattered granulomas, not sufficient burden

of disease– Cholestasis due to fungal infection generally a manifestation of

disseminated disease, fulminant process• Histoplasma, cryptococcus, blastomycosis, candida

– Case reports of biliary duct obstruction by fungus ball– Fungal infection likely acquired in hospital, negative cultures

• Case reports of hepatic and pancreatic candidal infections post-ERCP

• Pregnancy• Genetic• GVHD• Transplant rejection• TPN

What’s left?

• Paraneoplastic (RCCA -- Stauffer’s syndrome, NHL, HD, prostate)– Poorly understood pathophysiology – inflammatory cascade?– Not previously described in urothelial carcinoma– No mets identified– Up to 50% of patients with T2 or higher stage urothelial

carcinoma are eventually found to have metastatic disease• Medication effect

– Our patient exposed to at least 2 medications known to cause cholestasis

Drug Induced Liver Injury

• Dr. Jonathan Koff, Director, WRAMC Liver Clinic

DefinitionDefinition

• Liver injury caused by drugs or other chemicals, including complementary or alternative remedies

• There is no single diagnostic test– Diagnosis requires a high index of suspicion and judicious use of

diagnostic lab and imaging tests

• A diagnosis of exclusion (causality difficult to prove)

IncidenceIncidence

• One of the most frequent types of adverse reactions to pharmaceuticals and other chemicals

• 2-5% of patients hospitalized for jaundice• More than 40% of “hepatitis” in persons over age 50 years

old• Major cause of acute liver failure

General Mechanisms Underlying InjuryGeneral Mechanisms Underlying Injury

Drug (xenobiotic) Stable metabolites, excretion

P450 bioactivationP450 bioactivation

DetoxificationDetoxification

Reactive Reactive metabolitemetabolite

Immune Immune mechanismsmechanisms

Nonimmune Nonimmune mechanismsmechanisms

Cell damage

ClassificationClassification

Feature Intrinsic IdiosyncraticDose - dependent Yes No

Predictable Yes No

Genetic No Yes

Type of reaction Hepatocellular Cholestatic /

Mixed

Cause Toxic

Metabolite

Aberrant metabolite; Hypersensitivity

Examples Acetaminophen

Carbon tetrachloride

NSAIDs, Statins, Bactrim, Amoxicillin / Clavulanate, phenytoin

Hypersensitivity ReactionsHypersensitivity Reactions

• Idiosyncratic• Production of intermediate metabolite (immunoallergen)• Systemic immunologic reaction:

– Fever– Rash– Eosinophilia

• Examples:– Phenytoin, Halothane, Sulfonamides

Metabolic IdiosyncrasyMetabolic Idiosyncrasy

• Drug metabolized to toxic intermediary in small proportion of patients

• No signs of hypersensitivity• Latent period is unpredictable• Liver injury can occur 1 week to 1 year after starting

medication• Prototype drug - isoniazid

Risk factorsRisk factors

• Age:– More common in persons > 50 y.o.– More severe in persons > 50 y.o.

• Gender:– Women at increased risk v. men

• Obesity• Chronic alcohol use• Patients with previous hepatotoxicity• Use of multiple drugs

Subclinical liver diseaseSubclinical liver disease

• Injury reflected by elevation in serum liver enzymes– Aminotransferases and Alkaline phosphatase

• May occur in 5-50% of patients• Elevations (<3 times ULN):

– May resolve spontaneously– Drug may be continued if chemistries monitored

AminotransferasesAminotransferases

• Elevations > 3-5 x ULN are associated with significant liver injury when:– Observed in > 3% of study population– Occur with any elevation in serum bilirubin (10% chance of

severe liver injury)• Elevations > 10 x ULN rarely occur spontaneously and

are highly significant in any patient

Pre-existing Liver DiseasePre-existing Liver Disease

• Does not increase risk of drug toxicity:– Most drug reactions – idiosyncratic– Related to production of metabolites

• If toxicity does occur:– May be more severe– But only with advanced liver disease

• Exceptions:– Methotrexate– Chemotherapeutic agents

AcuteAcute

Hepatocellular CholestaticHepatocellular Cholestatic

ChronicChronic

Hepatocellular Cholestatic Vascular NeoplasticHepatocellular Cholestatic Vascular Neoplastic

Steatosis Phospholipidosis Fibrosis GranulomasSteatosis Phospholipidosis Fibrosis Granulomas

Spectrum of InjurySpectrum of Injury

Hepatocellular v. Cholestatic Hepatocellular v. Cholestatic ReactionsReactions

Feature Hepatocellular Cholestatic

Enzyme elevations AST / ALT ALP

Jaundice + / - + + / -

Pruritis No Yes

Acute liver failure Yes Rare

Case fatality rate Up to 10 % < 1 %

Acute Liver Failure: EtiologyAcute Liver Failure: Etiology

17%13%

4%

7%

6%

4%

10%

39%Acetaminophen

Indeterminate

Idiosyncratic drug

Hepatitis A

Hepatitis B

Ischemic

Autoimmune

Other

Ostapowitz G et al. Ann Inter Med 2002;137:947

Acute Liver Failure: DefinitionAcute Liver Failure: Definition

Rapid onset of Rapid onset of hepatic hepatic encephalopathyencephalopathy with severe with severe coagulopathycoagulopathy occurring within weeks occurring within weeks of symptoms or jaundice in a patient of symptoms or jaundice in a patient without pre-existing liver diseasewithout pre-existing liver disease

EpidemiologyEpidemiology

• 2000-2500 cases per year in U.S.• 300-350 emergency liver transplants for ALF per year• Case fatality rate 57% to 80% without transplant

Contraindications to Liver Contraindications to Liver TransplantationTransplantation

• Medical– Hepatic malignancy (too large or too many)– Cholangiocarcinoma– Extrahepatic malignancy – Active sepsis– Advanced cardiopulmonary disease– Active alcoholism or substance abuse– Irreversible brain damage caused by liver failure

• Surgical– Complete thrombosis of portal venous circulation

Cholestasis: MedicationsCholestasis w/o hepatitis

Cholestasis w/ hepatitis

Cholestasis w/ bile duct injury

Vanishing bile duct syndrome

Sclerosing cholangitis-like

Estrogens

Anabolic steroids

Cyclosporine

Tamoxifen

Azathioprine

Chlorpromazine

Macrolide antibiotics

Tricyclic anti-depressants

Carbamazepine

Amoxicillin-clavulanate

Oxypenicillins

NSAIDs

Azathioprine

Dextropropoxyphene

Flucoxacillin

Carmustine

Toxins: paraquat, methylene-dianiline

Chlorpromazine

Flucloxacillin and other oxypenicillins

Amoxicillin-clavulanic acid   Ampicillin 

Amitriptyline  

Azathioprine

Barbiturates

Carbamazepine

Chlorthiazide

Cotrimoxazole  

Clindamycin  

Chlorpromazine  

Cimetidine  

Cyproheptadine  

Dicloxacillin  

Erythromycin esters Estradiol  

Flucloxacillin  

Haloperidol  

Ibuprofen  

ImipramineD-penicillamine  

Phenytoin  

Norandrostenolone  

Prochlorperazine  

Tetracycline  

Terbinafine  

Thiabendazole 

Tiopronin 

Tolbutamide

Methyl testosterone 

Floxuridine

Intralesional scolicidal agents (2% formaldehyde, 20% hypertonic saline, absolute alcohol, silver nitrate, iodine solution)

Critical Exposure?

• Imipramine– Prescribed in the weeks following cystoprostatectomy for

incontinence– Timing of exposure could account for cholestasis progressing to

cholecystitis and subsequent chain of events

• Amoxicillin-clavulanate– Common cause of drug-induced cholestasis– At least part of patient’s clinical syndrome seems to have started

prior to exposure– Unclear how much of drug taken

• 2 hits?– Rare sensitivity to 2 drugs?

Literature Review Augmentin-induced Cholestasis

• First marketed in 1984– First case report of cholestatic hepatopathy in 1988

• Widely prescribed - 1/78209 prescriptions is Augmentin• Garcia et al. (1996) estimated risk of significant hepatic

injury at 1/100,000 patients exposed – 80%+ of cases with a cholestatic injury pattern– Also associated with sialadenitis and AIN

• Retrospective cohort study by Rodriguez et al. found risk of cholestatic liver injury to be 1.7/10,000 patients – Found a 5X increased risk of liver injury for Augmentin versus

Amoxicillin alone (1.7/10,000 vs 0.3/10,000)

Literature Review Augmentin-induced Cholestasis

• Both studies noted similar trends:– At greater risk: males, 60+yo, more than one exposure– Latency period: few days to 1 month– 75-80% present with cholestatic injury pattern: jaundice, pruritis,

less frequent N/V

• Striker et al., comment on the incidence of unnecessary cholecystectomies performed on patients with Augmentin cholestasis

• Larrey et al., note association of Augmentin cholestasis and liver biopsies showing granulomatous hepatitis

Literature Review Imipramine Cholestasis

• TCA’s: Imipramine and Amitryptiline

– Fewer case reports in the literature • Probably due to fewer prescriptions, TCAs falling out of favor w/

clinicians due to serious side effect profile

• Cholestatic injury pattern and hepatocellular necrosis

– Described as a “chronic cholestasis” process, usually with at least 1 month latency period between use and presentation

– Self-limited, very rare case reports of fulminant hepatic failure

Literature Review: Summary

• Case series/reports of drug-induced cholestasis causing liver failure and death– Most cases are self-limited, resolve with discontinuation of

offending agent– Rarely, patients can develop progressive disease– No clear risk factors for progressive disease identified

• Idiosyncratic drug reactions comprise almost 12% of all cases of acute liver failure (ALF Study Group)– Most ALF w/ hepatocellular injury pattern, not cholestasis

Treatment?

• Discontinuation of offending agent• Supportive therapy• No definitive therapy if cholestasis is progressive

– Steroids? Cholestyramine? Ursodeoxycholic Acid?• Only O’Brien et al (1996) reported success with ursodeoxycholic

acid in treating drug-induced cholestasis

• Transplant must be considered early for progressing cholestasis– Our patient was considered for transplant at Mt. Sinai in NYC,

but died before transfer

References

Garcia Rodriguez, L.A., et al. 1996. Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Medicine. 1996;156: 1327-32.

Horst, D.A., et al. 1980. Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy. Gastroenterology. 1980; 80: 550-4.

Larrey D., et al. 1992. Hepatitis associated with amoxicillin-clavulanic acid combination: report of 15 cases. Gut. 1992;33: 368-71.

Lee, W.M., et al. 2003. Drug induced hepatotoxicity. N Engl J Med. 2003;349: 474-485.

O’Brien, C.B., et al. 1996. Drug induced vanishing bile duct syndrome: response to ursodiol. Am J Gastroent. 1996;123: 161-7.

Mohi-ud-din, J.H., et al. 2004. Drug-and chemical-induced cholestasis. Clin Liver Dis 2004;8: 95-132.

Striker B.H., et al. 1989. Cholestatic hepatitis due to antibacterial combination of amoxicillin and clavulanic acid (Augmentin). Dig Dis Sci. 1989;34: 1576-80.