““Just” an alcoholic Just” an alcoholic hepatitis?hepatitis?

August 2005August 2005

White 10, Team C – Massachusetts General White 10, Team C – Massachusetts General Hospital,Hospital,

Boston – MA, USABoston – MA, USA

Lorenzo AzzaliniLorenzo Azzalini University of Padua University of Padua Medical School, ItalyMedical School, Italy

History of present illnessHistory of present illness 39 y.o. man w/ history of depression, 39 y.o. man w/ history of depression,

HTN, alcoholismHTN, alcoholism Admitted on 8/1 after a LOC, in a setting Admitted on 8/1 after a LOC, in a setting

of EtOH withdrawal, severe dehydration, of EtOH withdrawal, severe dehydration, hyponatremia, hypochloremia and ARF.hyponatremia, hypochloremia and ARF.

One month later, he is still in the One month later, he is still in the hospital.hospital.

Persistent hyperbilirubinemia, Persistent hyperbilirubinemia, leukocytosis and fever of unclear etiologyleukocytosis and fever of unclear etiology

Intubated, NG tube, IV hydration and Intubated, NG tube, IV hydration and electrolytes disturbances correctionelectrolytes disturbances correction

On 8/2, transfer to the MICU.On 8/2, transfer to the MICU.

History of present illnessHistory of present illness Broad spectrum antibiotic treatment: Broad spectrum antibiotic treatment:

ampicillin, levofloxacin, flagyl (ampicillin, levofloxacin, flagyl ( afebrile but left shift w/o clear source of afebrile but left shift w/o clear source of infection: risk for aspiration but clear infection: risk for aspiration but clear CXR, U/A –ve)CXR, U/A –ve)

Agitation, tachycardia and confusion Agitation, tachycardia and confusion given propofol and intubatedgiven propofol and intubated

Diagnosis of alcoholic hepatitis (Diagnosis of alcoholic hepatitis (AST AST and ALT, AST/ALT > 2, and ALT, AST/ALT > 2, bilirubin and bilirubin and Alk Phos).Alk Phos).

8/9: transfer to White 108/9: transfer to White 10

History of present illnessHistory of present illness On White 10 the patient regained On White 10 the patient regained

consciousness. Denied abdominal consciousness. Denied abdominal pain, and was unable to recall much pain, and was unable to recall much about the events that led up to his about the events that led up to his admissionadmission

The pt reported that he was The pt reported that he was depressed and had drunk heavily in depressed and had drunk heavily in the last weeks. He had lost his the last weeks. He had lost his appetite and had been eating almost appetite and had been eating almost nothing, and – in spite of that – had nothing, and – in spite of that – had been vomiting frequentlybeen vomiting frequently

Review of systemsReview of systems Nausea/vomiting.Nausea/vomiting. Alteration of mental status, slurring of speech.Alteration of mental status, slurring of speech.

Past medical historyPast medical history

Alcoholism and depressionAlcoholism and depression Hypertension Hypertension – borderline– borderline ?Sarcoidosis?Sarcoidosis – Presumptive – Presumptive

diagnosis, based on CXR and chest CTdiagnosis, based on CXR and chest CT

Meds on admission to Meds on admission to White 10White 10 Lisinopril 10 mg PO QDLisinopril 10 mg PO QD

Vancomycin 1 g IV Q12 (since 8/9)Vancomycin 1 g IV Q12 (since 8/9) Cefepime 1 g IV Q12 (since 8/8)Cefepime 1 g IV Q12 (since 8/8) Flagyl 500 mg PO TID (since 8/1)Flagyl 500 mg PO TID (since 8/1) Nexium 40 mg PO BIDNexium 40 mg PO BID Neutra-Phos 2.5 g PO TIDNeutra-Phos 2.5 g PO TID Lactulose 30 ml PO QIDLactulose 30 ml PO QID Ativan 4mg IV Q3Ativan 4mg IV Q3 Ativan 1-2 mg IV Q1 PRN Ativan 1-2 mg IV Q1 PRN Haldol 2 mg IV Q4 PRNHaldol 2 mg IV Q4 PRN Thiamine 100 mg PO QDThiamine 100 mg PO QD MVIMVI Fragmin 2500 U sc QDFragmin 2500 U sc QD Senna and colaceSenna and colace

AllergiesAllergies – NKDA – NKDA Social historySocial history – – Works in publishing, fired 2 Works in publishing, fired 2

weeks prior to admission. Recently separated weeks prior to admission. Recently separated from his wife because his of EtOH use, from his wife because his of EtOH use, undergoing divorce. Has a 6-year-old son. undergoing divorce. Has a 6-year-old son. Lives alone.Lives alone.

Familial historyFamilial history – – father w/ HTN, mother w/ father w/ HTN, mother w/

?chemical dependency?chemical dependency Physical examPhysical exam

Unremarkable, except for:Unremarkable, except for: HR 107, RR 24HR 107, RR 24 the patient was in mild distress (spoke slowly, the patient was in mild distress (spoke slowly,

interrupted his words to breath)interrupted his words to breath) a JVP of 7 cma JVP of 7 cm abdominal distensionabdominal distension

Labs and Studies on Labs and Studies on admissionadmission

Total bilirubin 8.8, direct bilirubin Total bilirubin 8.8, direct bilirubin 5.05.0

Albumin 2.2Albumin 2.2 AST 140, ALT 66, Alk Phos 188AST 140, ALT 66, Alk Phos 188 HCT 29%, Hgb 10HCT 29%, Hgb 10 WBC 26 (N 86, L 9)WBC 26 (N 86, L 9)

Bilirubin during the month of August

05

1015202530

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29

Days

Bilir

ubin

(mg/

dl)

Direct Bilirubin

Total Bilirubin

WBC during the month of August

0

10

20

30

40

50

60

70

801 3 5 7 9

11 13 15 17 19 21 23 25 27 29 31

Days

WB

C (x

1000

/mm

3)

neutrophils, lymphocytes

Chest X-Ray and CTChest X-Ray and CT Increased consolidation in the RUL, RML and LLL Increased consolidation in the RUL, RML and LLL

concerning for aspiration or multifocal pneumonia.concerning for aspiration or multifocal pneumonia. StableStable right pleural effusion with associated right pleural effusion with associated

atelectasis. atelectasis. Chest CT negative for pneumonia, confirmed the Chest CT negative for pneumonia, confirmed the

presence of bilateral pleural effusionspresence of bilateral pleural effusions

Abdomino-pelvic CTAbdomino-pelvic CT No specific evidence for pancreatitis or its No specific evidence for pancreatitis or its

complicationscomplications Increasing ascitesIncreasing ascites Increasing bilateral pleural effusionsIncreasing bilateral pleural effusions

Abdominal USAbdominal US Fatty infiltration of the liver.Fatty infiltration of the liver. Distended and thickened gallbladder.Distended and thickened gallbladder. Small amount of ascites in the abdomen Small amount of ascites in the abdomen

and pelvisand pelvis

Other studiesOther studies ECGECG: Sinus tachycardia: Sinus tachycardia Head and brain CTHead and brain CT: No evidence of : No evidence of

intracranial hemorrhage. No fractures intracranial hemorrhage. No fractures seenseen

EEGEEG: Markedly abnormal EEG, due to the : Markedly abnormal EEG, due to the presence of diffuse, attenuated delta presence of diffuse, attenuated delta slowing without focal features. No slowing without focal features. No epileptiform activity is presentepileptiform activity is present

Blood cultureBlood culture: no growth after 7 days.: no growth after 7 days.

Assessment and planAssessment and plan

39 y.o. man with history of depression 39 y.o. man with history of depression and alcoholism, presenting with EtOH and alcoholism, presenting with EtOH withdrawal syndrome, in a setting of withdrawal syndrome, in a setting of severe dehydration, metabolic severe dehydration, metabolic alkalosis, hyponatremia, alkalosis, hyponatremia, hypochloremia and pre-renal ARF.hypochloremia and pre-renal ARF.

1)1) Electrolytes disturbancesElectrolytes disturbances Monitor lytesMonitor lytes Continue IV hydration until full POContinue IV hydration until full PO

Assessment and planAssessment and plan

2)2) Mental statusMental status All work up has been negative: CT, LP, EEGAll work up has been negative: CT, LP, EEG On MVIsOn MVIs ?Psychiatric disturbance ?Psychiatric disturbance consider consider

psychiatry consult, when 'stable‘psychiatry consult, when 'stable‘

3)3) LeukocytosisLeukocytosis Unknown etiology Unknown etiology on broad spectrum on broad spectrum

antibiotics: cefepime, flagyl and vancomycinantibiotics: cefepime, flagyl and vancomycin Blood, sputum and urine cultures pendingBlood, sputum and urine cultures pending CXR read as c/w aspiration pneumonia CXR read as c/w aspiration pneumonia

continue antibiotics for now and repeat CXR continue antibiotics for now and repeat CXR later onlater on

Assessment and planAssessment and plan

4)4) HyperbilirubinemiaHyperbilirubinemia Unclear etiology. Abdomen US reveals Unclear etiology. Abdomen US reveals

fatty liver; CT shows worsening ascites, no fatty liver; CT shows worsening ascites, no evidence of pancreatitis. No evidence of evidence of pancreatitis. No evidence of hemolysis (haptoglobin normal)hemolysis (haptoglobin normal)

Work up for cirrhosis, hepatitis serologies, Work up for cirrhosis, hepatitis serologies, ceruloplasmin, iron studies, ANAceruloplasmin, iron studies, ANA

5)5) EtOh withdrawal/tachycardiaEtOh withdrawal/tachycardia Ativan 4 mg IV Q4Ativan 4 mg IV Q4

6)6) ARFARF Resolved with hydrationResolved with hydration

Differential diagnosisDifferential diagnosis

JaundiceJaundice Alcoholic liver diseaseAlcoholic liver disease Viral hepatitisViral hepatitis IV drugs? Sexual IV drugs? Sexual

promiscuity? Travel to endemic area?promiscuity? Travel to endemic area? HemolysisHemolysis rarely raises the rarely raises the

bilirubin over 5 mg/dl. Look for an bilirubin over 5 mg/dl. Look for an increased reticulocyte count, indirect increased reticulocyte count, indirect bilirubin and LDH.bilirubin and LDH.

Primary biliary cirrhosisPrimary biliary cirrhosis middle middle aged woman, with jaundice, fatigue, aged woman, with jaundice, fatigue, pruritus. AMA + elevated Alk Phos + pruritus. AMA + elevated Alk Phos + elevated IgM.elevated IgM.

SepsisSepsis diagnosis of exclusion. diagnosis of exclusion.

Differential diagnosisDifferential diagnosis

Leukocytosis and feverLeukocytosis and fever Persistent infectionsPersistent infections Mycobacterial or fungal infectionsMycobacterial or fungal infections NeoplasmsNeoplasms solid tumors and solid tumors and

lymphoproliferative disorderslymphoproliferative disorders Primary hematologic disordersPrimary hematologic disorders

myeloprolipherative disorders (e.g., myeloprolipherative disorders (e.g., polycythemia vera), leukemias, chronic polycythemia vera), leukemias, chronic hemolysishemolysis

Chronic inflammation statesChronic inflammation states rheumatic fever, SLE, thyroiditis, rheumatic fever, SLE, thyroiditis, myositis, drug reactions, pancreatitismyositis, drug reactions, pancreatitis

Work upWork up Liver function testsLiver function tests acute acute

hepatitis, sepsis, leukemia, hepatitis, sepsis, leukemia, lymphoma, metastatic carcinomalymphoma, metastatic carcinoma

AmylaseAmylase significant elevations significant elevations (>10 times the normal values) are (>10 times the normal values) are suggestive of biliary diseasesuggestive of biliary disease

Hepatitis serologyHepatitis serology HBsAg, IgM HBsAg, IgM anti-HBcAg, IgM anti-HAV, Ig anti-anti-HBcAg, IgM anti-HAV, Ig anti-HCVHCV

Other testsOther tests ANA, AMA, SMA, ANA, AMA, SMA, ceruloplasmin, iron studies, ceruloplasmin, iron studies, 11--antitrypsinantitrypsin

Work upWork up Blood analysis and blood smearBlood analysis and blood smear

quantitative and/or qualitative quantitative and/or qualitative alterations of blood cellsalterations of blood cells

CulturesCultures blood, urine, CSF, blood, urine, CSF, sputum (to r/o infectious cause)sputum (to r/o infectious cause)

Abdomen CT +/- USAbdomen CT +/- US to r/o to r/o cholelythiasis, cholecystitis, cholelythiasis, cholecystitis, pancreatitis, etcpancreatitis, etc

ERCP or PTCERCP or PTC if an extra-hepatic if an extra-hepatic obstruction is suspectedobstruction is suspected

CT scansCT scans abscess, masses, LAD, abscess, masses, LAD, organomegaly, other types of lesionsorganomegaly, other types of lesions

Work upWork up Chest X-rayChest X-ray acute pneumonia, acute pneumonia,

masses, mediastinal abnormalitymasses, mediastinal abnormality Tumor markersTumor markers leukocyte alkaline leukocyte alkaline

phospatase (LAP), vit Bphospatase (LAP), vit B1212 levels, tests levels, tests for monoclonal Ab to carcinomasfor monoclonal Ab to carcinomas

Bone marrow aspiration and biopsyBone marrow aspiration and biopsy to exclude a primary bone marrow to exclude a primary bone marrow disorder, metastatic tumor, chronic disorder, metastatic tumor, chronic infectionsinfections

HyperbilirubinemiaHyperbilirubinemia Liver Team consult Liver Team consult confirmed our diagnosis confirmed our diagnosis

of alcoholic hepatitis. Persistent Alk Phos and of alcoholic hepatitis. Persistent Alk Phos and bilirubin high levels were still of unclear bilirubin high levels were still of unclear etiology.etiology.

HCV and HBV serologies were negative.HCV and HBV serologies were negative. ANA were negative. No evidence of ANA were negative. No evidence of

autoimmune hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary biliary cirrhosis, Wilson’s diasease, hemochromatosis, or Wilson’s diasease, hemochromatosis, or 11--antitrypsin deficiency.antitrypsin deficiency.

HIDA scan HIDA scan wrong indication (no excretion of wrong indication (no excretion of tracer due to hepatic insufficiency).tracer due to hepatic insufficiency).

Cholecystotomy tube Cholecystotomy tube presumptive acalculus presumptive acalculus cholecystitis. No improvement of jaundice. cholecystitis. No improvement of jaundice. Bilirubin even increased.Bilirubin even increased.

Infection?Infection?

Pt treated with broad spectrum Pt treated with broad spectrum antibiotics in the MICU for presumptive antibiotics in the MICU for presumptive sepsis.sepsis.

On White 10, antibiotics were stopped, as On White 10, antibiotics were stopped, as sepsis was not likely. Cefepime and sepsis was not likely. Cefepime and vancomycin were used for 5 days upon a vancomycin were used for 5 days upon a diagnosis of aspiration pneumonia.diagnosis of aspiration pneumonia.

Blood, urine, CSF, pleural liquid, bile, Blood, urine, CSF, pleural liquid, bile, ascitic liquid, sputum cultures were ascitic liquid, sputum cultures were repeatedly negative.repeatedly negative.

Infection?Infection? During the whole hospitalization, the pt’s During the whole hospitalization, the pt’s

temperature remained almost always temperature remained almost always between 98 and 101between 98 and 101°F°F. When antibiotics . When antibiotics were d/c, there was an increase of the were d/c, there was an increase of the temperature. But neither the leukocytosis temperature. But neither the leukocytosis nor the hyperbilirubinemia were nor the hyperbilirubinemia were influenced by the antibiotic treatment.influenced by the antibiotic treatment.

For this reason, For this reason, ID ruled out infection ID ruled out infection as a possible etiology of the pt’s fever, as a possible etiology of the pt’s fever, leukocytosis and hyperbilirubinemia.leukocytosis and hyperbilirubinemia.

Hematologic disorder?Hematologic disorder?

Hematology consultHematology consult TThis patient’s anemia is likely anemia his patient’s anemia is likely anemia

of chronic disease (low TIBC and high of chronic disease (low TIBC and high ferritin) or some marrow suppression ferritin) or some marrow suppression in the setting of infection and in the setting of infection and inflammation.inflammation.

Macrocytic anemia of vitamin BMacrocytic anemia of vitamin B1212 and and folate deficiency is a possibility (MCV folate deficiency is a possibility (MCV in the upper limit of normal interval).in the upper limit of normal interval).

Although the patient has elevated Although the patient has elevated bilirubin and appears icteric, he is bilirubin and appears icteric, he is unlikely to have a hemolytic process (as unlikely to have a hemolytic process (as his haptoglobin and LDH are normal).his haptoglobin and LDH are normal).

Hematologic disorder?Hematologic disorder? The leukocytosis is likely a leukemoid The leukocytosis is likely a leukemoid

reaction in the setting of chronic reaction in the setting of chronic inflammation or infection.inflammation or infection.

Other considerations on the differential Other considerations on the differential diagnosis of leukocytosis include CML, diagnosis of leukocytosis include CML, hematologic and non-hematologic hematologic and non-hematologic malignancies.malignancies.

To differentiate CML from a leukemoid To differentiate CML from a leukemoid reaction reaction leukocyte alkaline leukocyte alkaline phosphatase (LAP) score:phosphatase (LAP) score:• high in infection, inflammation, and high in infection, inflammation, and

polycythemia vera (PV)polycythemia vera (PV)• low in chronic myelogenous leukemia low in chronic myelogenous leukemia

(CML)(CML)

Hematologic disorder?Hematologic disorder? When the marrow is directly invaded by When the marrow is directly invaded by

tumor, fibrosis, or granulomatous reactions, tumor, fibrosis, or granulomatous reactions, neutrophilia can be associated with neutrophilia can be associated with circulating immature granulocytes, nucleated circulating immature granulocytes, nucleated red cells, and teardrop-shaped erythrocytes, red cells, and teardrop-shaped erythrocytes, with or without thrombocytosis.with or without thrombocytosis.

Leukocyte alkaline phospatase (LAP) score Leukocyte alkaline phospatase (LAP) score 89 (normal: 40-100)89 (normal: 40-100)

Blood smear Blood smear normal (except for some normal (except for some target cells). target cells).

The combination of anemia and The combination of anemia and neutrophilia is often associated with neutrophilia is often associated with chronic infection or inflammation, and chronic infection or inflammation, and this is our leading diagnosis for this this is our leading diagnosis for this patient’s hematologic pathology.patient’s hematologic pathology.

?

A sad storyA sad story During the last days of August, the patient During the last days of August, the patient

developed hepato-renal syndrome (Cr 5.9 developed hepato-renal syndrome (Cr 5.9 mg/dl), massive ascites and hepatic mg/dl), massive ascites and hepatic encephalopathy; his blood cultures grew encephalopathy; his blood cultures grew gram +ve cocci. He was transferred to gram +ve cocci. He was transferred to the MICU.the MICU.

MELD score was 41 on 9/1 (calculated as MELD score was 41 on 9/1 (calculated as 91% mortality at 90 days per the Mayo 91% mortality at 90 days per the Mayo Clinic website calculator).Clinic website calculator).

Goals of care were discussed with the Goals of care were discussed with the family.family.