Stuart Cohen, MD

General Internal Medicine

Today’s speaker has no conflict of interest to disclose.

The University of Alabama School of Medicine is accredited by the Accreditation Council for

Continuing Medical Education to provide continuing medical education for physicians.

UAB School of Medicine designates this educational activity for a maximum of 1 AMA PRA

Category 1 Credit (s) Physicians should only claim credit commensurate with the extent of their

participation in the activity.

HPI

Young Vietnamese woman

Fever, chills, nausea, diarrhea x 2 weeks

Abdominal pain with distension x several days

No benefit from 5 days of Azithromyacin

No arthralgias or rash

No NSAID or Tylenol use

No change in Medicines

Significant PMhx SLE (5 yrs)

CKD (focal sclerosing lupus nephritis)

preeclampsia with fetal demise

Hypertension

hyperlipidemia Meds

Prednisone (Prednisone 30 mg every other day)

Hydroxychloroquine

Rosuvastatin

Diltiazem

Furosemide

Social Hx

Married, lives in Auburn, Al.

Undergraduate and works at a pharmacy

No tobacco, alcohol or drug use

Visited Vietnam for 1 month – (5 months ago)

PE Temp 97.5, BP 127/75, P 111, RR 22, O2 sat 99%

Ill- appearing, A&O x 4

HEENT

▪ Small ulceration over left upper lip

Chest- CTAB

C/V- tachycardic with r/r/r, No S3

Abdomen

▪ protuberant, tense , tender and dull to percussion. Mild hepatomegaly, No splenomegaly

M/S

▪ R wrist and B knees with effusions but non-tender

Neuro- CN 2-12 intact, no focal deficits

LABS

BUN 62, Cr 4.7 (baseline 2.0)

WBC 5.5, HCT 26, PLT 7K (diff 80s, 4l, 16m)

TBILI 5.3 (3.8 direct) AST 6009, ALT 4905

PT 41, PTT 92, INR 4.0

D-Dimer > 20K, Fibrinogen 105

Tprot 3.2, Alb 1.5, AP 131

C3 62, C4 11.6

Special labs HBsAG neg, HBsAb pos

HCV Ab neg, HCV VL neg

HEV neg

HIV neg

EBV IgG pos, IgM neg

CMV IgG pos, IgM neg

ANA >1:80, ASMA neg, AMA neg

NH4 50, Lactic Acid 4

Ceruloplasmin 14, Acet <14, Salicylate 7.0

Labs

FE 229, TIBC 118, Ferritin 6334, Fe %sat 195,

LDH 5700, retic 1.6%

Peripheral Smear: No schistocytes, no

clumped platelets

Liver Biopsy: Areas of hepatocellular necrosis

with fragments of preserved hepatocytes

Acute liver injury

Acute on chronic renal failure

Severe thrombocytopenia

Coagulopathy

Normocytic anemia

14th-century English logician, theologian

and Franciscan friar, William of Ockham

“the simplest explanation or strategy

tends to be the best one”

Exacerbation of a pre-existing disease

Complication of a pre-existing disease

New problem

Acute Liver Failure

Rapid development of severe acute liver injury with

impaired synthetic function and encephalopathy in a

person who previously had a normal liver or had well-

compensated liver disease.

Fulminant Liver failure

Encephalopathy w/in 8 weeks of onset of symptoms

Encephalopathy w/in 2 weeks of developing jaundice

Subfulminant liver failure

Encephalopathy within 6 months of onset of

symptoms

A Acetaminophen, hepatitis A, autoimmune

hepatitis

B Hepatitis B

C Cryptogenic, hepatitis C

D Hepatitis D, drugs

E Esoteric causes - Wilson's disease, Budd-Chiari

syndrome

F Fatty Infiltration - acute fatty liver of pregnancy,

Reye's syndrome

Viruses

Hepatitis A, B, C, D, E

EBV, CMV, HSV, VZV

Drugs/Toxins

Acetaminophen, other

Drugs

Carbon Tetrachloride

poisonous mushrooms

Vascular

Budd Chiari syndrome

Ischemic Hepatitis

Metabolic

Wilson’s disease

Acute Fatty liver of

pregnancy

Reye’s syndrome

Miscellaneous

Autoimmune Hepatitis

Malignant infiltration

Sepsis

Viruses

Hepatitis A, B, C, D, E

EBV, CMV, HSV, VZV

Drugs/Toxins

Acetaminophen, other

Drugs

Carbon Tetrachloride

poisonous mushrooms

Vascular

Budd Chiari syndrome

Ischemic Hepatitis

Metabolic

Wilson’s disease

Acute Fatty liver of

pregnancy

Reye’s syndrome

Miscellaneous

Autoimmune Hepatitis

Malignant infiltration

Sepsis

Viruses

Hepatitis A

HSV, VZV

Drugs/Toxins

Vascular

Budd Chiari syndrome

Ischemic Hepatitis

Metabolic

Wilson’s disease

Miscellaneous

Autoimmune Hepatitis

Malignant infiltration

Sepsis

Viruses

Hepatitis A

HSV, VZV

Drugs/Toxins

Vascular

Budd Chiari syndrome

Ischemic Hepatitis

Metabolic

Wilson’s disease

Miscellaneous

Autoimmune Hepatitis

Malignant infiltration

Sepsis

Viruses

Hepatitis A

HSV, VZV

Drugs/Toxins

Vascular

Budd Chiari syndrome

Metabolic

Wilson’s disease

Miscellaneous

Autoimmune Hepatitis

HAV infection usually results in an acute,

self-limited illness and only rarely leads to

fulminant hepatic failure

Fulminant hepatic failure occurs more

commonly in patients with underlying liver

disease, particularly chronic hepatitis C

virus infection

Two most common Physical findings

Jaundice (70%)

Hepatomegaly (80%)

Extrahepatic manifestations associated

with acute HAV infection include

vasculitis, arthritis, optic neuritis, transverse

myelitis, thrombocytopenia, aplastic anemia,

and red cell aplasia

Marked elevations of

serum aminotransferases (usually >1000

IU/dL)

serum total and direct bilirubin

alkaline phosphatase

ALT is commonly higher than the AST

Serum bilirubin levels above 10 mg/dL are

common

Acetaminophen is most common toxin associated with ALF (usually in Suicide attempt) 8-30% cases occur with therapeutic use

Aggravated by▪ Alcohol consumption

▪ Antiepileptic therapy (enzyme induction)

▪ Malnutrition

Idiosyncratic drug reactions causing ALF usually occur during first exposure 0.001% for NSAIDs

1% for Isoniazid/Rifampin combination

First described in the 1950s

Chronic hepatitis of unknown etiology

characterized by the presence of

circulating autoantibodies and high serum

globulin concentrations

Clinical manifestations

Marked variability ranging from asymptomatic

to fulminant hepatic failure

Physical findings

Range from Normal PE to hepato-

splenomegaly with stigmata of chronic liver

disease

Diseases commonly associated

hemolytic anemia

ITP

T1 DM

Thyroiditis

Celiac sprue, and ulcerative colitis

AST/ALT elevations are more striking than those of bilirubin and AlkPhos

Elevation in serum globulins, particularly IgG

• Diagnosis is based upon characteristic serologic and

histologic findings and exclusion of other forms of

chronic liver disease

Histology

Periportal mononuclear cell infiltrate

(piecemeal necrosis) extending into the lobule

An exuberant plasma cell infiltrate without

granuloma formation

Fibrosis is present in all but the mildest cases

Distinct from Autoimmune Hepatitis,

drugs, toxins or viral

Given Lupus patients prone to hepatitis

from vast variety of etiologies, it can be

very difficult to distinguish…

Characterized by Ribosomal P protein

antibodies

Definition

Any pathophysiologic process that results in

interruption of the normal blood flow out of the

liver

implies thrombosis of the hepatic veins and/or

the intrahepatic or suprahepatic inferior vena

cava

median age 35 (range 13 to 76) 67 % were female myeloproliferative disorder was present in 23

percent The two most common symptoms were

ascites (84 percent)

hepatomegaly (76 percent)

The hepatic outflow obstruction

hepatic veins (62 percent)

inferior vena cava (7 percent)

both (31 percent)Hepatology 2004 Feb;39(2):500-8.

Acute — Abdominal pain with ALT> 5x normal and

liver cell loss at bx -- (20 %)

Subacute -- having signs or symptoms for less than

six months and no evidence of liver cirrhosis — (40

%)

Chronic -- having signs or symptoms for more than

six months with evidence of portal hypertension and

cirrhosis — (40 %)

Occurs most commonly in women (often

during pregnancy)

Severe right upper quadrant pain and

hepatomegaly

Jaundice and ascites develop rapidly

Aminotranfserase elevation (100-600 IU/L)

Liver function can deteriorate quickly,

leading to hepatic encephalopathy and

liver failure

Histology

centrizonal congestion, necrosis, and

hemorrhage

Large regenerative nodules and obstructive

portal venopathy is common

Cirrhosis may be present in the chronic form

of the disease

An autosomal recessive defect in cellular copper

transport

prevalence of approximately 1 case in 30,000

live births in most populations

Impairment in biliary excretion leads to the

accumulation of copper in the liver

Over time the liver is progressively damaged

and eventually becomes cirrhotic.

The mean age was 16 years old. Predominant features

neurologic (69 percent)

hepatic (15 percent)

hepato-neurologic (2.5 percent)

pure psychiatric (2 percent)

asymptomatic (5 percent).

Kayser-Fleischer rings were seen more commonly in those with neurologic symptoms compared with those with predominant hepatic presentations

Asymptomatic liver function abnormalities

Portal hypertension Chronic hepatitis

Chronic hepatitis

Acute liver failure

Coombs-negative hemolytic anemia with

features of acute intravascular hemolysis

Coagulopathy unresponsive to vitamin K

Rapidly progressive renal failure

Serum aminotransferases typically less than

2,000 IU/L (AST often greater than ALT)

Normal or markedly subnormal alkaline

phosphatase (<40 IU/L)

Liver histology

Histologic findings are similar to those of

autoimmune hepatitis and nonalcoholic

steatohepatitis (NASH)

Early findings include fatty infiltration within

hepatocytes, glycogen inclusions within nuclei,

and portal fibrosis

Hepatitis due to disseminated HSV recognized for nearly 70 years

Occurs most commonly in neonates, and malnourished children

Remains a rare cause of ALF in adults < 1% of cases of fulminant hepatic failure

25-50 cases per year in the United States▪ 40% HSV1

▪ 60% HSV2

Often fulminant and fatal in part because the diagnosis is unexpected until autopsy Correct diagnosis made before autospy in < 25%

of patients

In adults, seen primarily in patients with

impaired immunity

Defects in cell-mediated immunity

Often secondary to organ transplantation

and/or steroid administration

Can occur in immunocompetent persons

In one series, comprised 24% of all cases

Large initial HSV inoculum overwhelms

defense system resulting in visceral

dissemination

Dissemination from mucosal lesion because of

impaired macrophage, cytotoxic T lymphocyte

and delayed-type hypersensitivity reaction

Virulence of HSV enhanced by activation of a

latent virus in association with reinfection by a

second strain of HSV

May be due to hepatovirulent strains

Symptoms Fever 82%

Severe abdominal pain 33%

Nausea and/or vomiting 18% Signs

Oral or genital lesions 57%

Hepatomegaly 45% Labs

Leukopenia 43%

Thrombocytopenia 45%

Coagulopathy with DIC 35%

Coagulopathy without DIC 20%

Kaufman,et al. Clinical Infectious Diseases. 1997;24:334-8

Renal Transplant 9 Use of Steroids 10 Polio 1 Pregnancy 9 Burns 2 Cancer 7 Thymic dysplasia 1 AIDS 1 Inhalational anesthetics 4 None 8

Kaufman,et al. Clinical Infectious Diseases. 1997;24:334-8

High index of suspicion is essential--must consider HSV in differential of ALF

Serologic testing for HSV is not very helpful secondary to high seroprevalence

HSV 1 62% (in persons 14-49 y/o in USA)

HSV2 17%

PCR can detect HSV DNA in serum (but often long delay in getting results)

Specificity 99%

Sensitivity 90%

Histology

Focal areas of necrosis with minimal surrounding inflammation

“Coagulative “necrosis is either randomly or centrilobular distributed with minimal portal involvement

Intranuclear viral inclusions are diagnostic and found in hepatocytes just beyond the edges of the necrotic lesions

Immunohistochemistry

Stains positive with antibody specific to HSV 1 and 2

Antivirals (Acyclovir)

Survival is 88% compared to 51% in those not

receiving Acyclovir

Those receiving Acyclovir sooner do better

than those receiving it later

Immunocompetent patients are less likely to

receive antivirals (due to delay in diagnosis)

Liver transplant is an option

Acute Liver Failure secondary to HSV-1

Diagnostic Procedure:

Immunostaining for HSV-1 antigen on the

Liver biopsy