Jaundice due to bacterial infection

GASTROENTEROLOGY

CLINICAL

CONFERENCE

Jaundice

Due to Bacterial

Infection

HYMAN J. ZIMMERMAN, Moderator CASE PRESENTOR: MARY FANG. DISCUSSANTS: RICCARDO UTILI, LEONARD and JAY HOOFNAGLE

B. SEEFF,

The Departments of Medicine, The V.A. Medical Center, The George Washington School of Medicine, The Georgetown University School of Medicine, Washington,

Jaundice

due to Bacterial

Infections

Systemic and extrahepatic infectious disease can lead to biochemical changes indicative of hepatic involvement and even to jaundice.lm3 For the most part the hepatic involvement is overlooked or recognized as an inconsequential component of an identified systemic illness. Furthermore, in the case of viral infections, misconstruing the illness as hepatic rather than systemic would not affect therapy significantly. Bacterial infection as a cause of jaundice, however, if overlooked would fail to receive appropriate therapy.’ Indeed, this appears to be particularly relevant to gram-negative bacterial infections, which are recognized by pediatricians to be an important cause of jaundice in infants.4-‘2 The icterogenie role of infections due to gram-negative bacteria in adults,2.3.‘3-‘7which is much less appreciated, is illustrated by a patient to be described by Dr. Fang. Case

History

DR. MARY

FANG*

The patient was a 45-year-old black female admitUniversity Hospital comted to the George Washington plaining of crampy lower abdominal pain, nausea, and vomiting for 2 wk. During the five days before admission, she had noted intermittent fever and chills, dysuria, and incontinence along with early satiety and anorexia. She

* Fellow, Gastroenterology The George D.C.

77:31x2-374,1979

Washington

Section, Department

University

Medical

Center,

of Medicine, Washington,

Received February 161979. Accepted March 27,1979. Address requests for reprints to: Hyman J. Zimmerman, M.D., Veterans Administration Hospital, 50 Irving St. NW, Washington, D.C. 20422.

University D.C.

had been well previously except for mild hypertension controlled with alpha-methyldopa 250 mg orally daily for many years. The patient gave a history of moderate alcohol intake but none over the previous 2 mo. On admission, she was febrile at 38’C, and had scleral icterus. There was mild tenderness in the epigastrium and left lower quadrant with voluntary guarding. The liver span was 10 cm by percussion with a palpable left lobe. She had left costovertebral angle tenderness. Laboratory studies revealed a hematocrit of 31%, white cell count of 9,286 rising to 14,366 with a differential of 78% polys and 6% bands; bilirubin 6.7 mg/dl; alkaline phosphatase 131 IU; SGOT 315 IU; albumin 2.3 g/dl. Urinalysis showed 15-20 WBC/hpf with 3-5 RBC/hpf and many bacteria. Figure 1 is a graphic representation of the patient’s bilirubin, SGOT, and alkaline phosphatase levels. Gentamicin and carbenicillin were started when blood cultures yielded a gram-negative bacillus. Ampicillin was substituted for the other antibiotics when the organism was identified as E. coli. Urine culture also yielded E. coli. Intravenous pyelogram showed poor excretory function of both kidneys. Abdominal sonogram revealed no gallstones and no evidence of extrahepatic biliary obstruction. Liver scan showed minimal hepatomegaly. The patient’s temperature initially increased to 39°C. As the acute pyelonephritis was treated, she defervesced, her symptoms resolved, and her liver function tests returned to normal values. Dr. Zimmerman: While jaundice is a known complication of nonhepatic infections due to gram-negative bacteria, the possibility that the jaundice in the patient under discussion was due to hepatobiliary disease and that the urinary tract infection was coincidental warrants consideration. The absence of other evidence for liver or biliary tree disease in our patient and the rapid, simultaneous remission of urinary tract infection and jaundice during antibiotic treatment strongly favor a direct relationship between the jaundice and the infection, Dr. Utili will discuss the role of gram-negative bacterial infection in causing jaundice.

August 19i’9

JAUNDICE

-1 400

01

INFECTION

O-

2

5

-0

10

15

20

25

Figure 1. EGochemical values during the course of illness in a patient with jaundice secondary to a gram-negative infection. Arrows indicate period of antibiotic therapy.

Jaundice in Gram-Negative Bacterial Infections DR. RICCARDO

UTILI’

The syndrome of jaundice, largely cholestatic, in patients with gram-negative bacterial infection, is well known to pediatricians. A review of the literature (Table 1) indicates that this syndrome is most frequent in the neonatal period and up to the age of 2 mo. The importance of this syndrome among infants is illustrated by one series of 76 patients with neonatal jaundice (other than that due to fetal-maternal blood group incompatability) in which bacterial infection was responsible for one-third of the cases,7 and by several series of cases of acute bacterial infection, in which the frequency of jaundice ranged from 6 to 60’X4.’ In adults, this syndrome occurs much less frequently and is usually mild’ except during severe sepsis3.‘4-‘8 or pregnancy.17 The most commonly reported agent and site of infection, in neonates, are E. coli and the urinary tract, respectively.‘-‘” In adults, however, many types of severe abdominal infections are reported to be responsible for this syndrome.1-3.‘4-‘7 Biochemical parameters demonstrate hyperbilirubinemia with a high percentage of the conjugated form, particularly after the first week of life. Alkaline phosphatase levels vary from minimal to marked elevations, and the transaminases are usually only minimally or moderately elevated. Our patient’s transaminases were somewhat higher, as tends to occur in adults whose cholestatic syndromes are provoked by bacteremic infections. In accord with the biochemical profile, liver histology reveals intrahepatic cholestasis with Kupff er cell hyperplasia and little or no evidence of cellular necrosis. Electron microscopic studies of liver biopsies have shown marked dilatation of the microvilli.‘“.” Visiting Scientist, Liver Research Laboratory, Veterans Administration Medical Center, Washington, D.C.; Assistant ProfesSOTat the Specialization School of Infectious & Tropical Disease, University of Naples, Italy.

363

Jaundice may be the only clinical sign of infection in neonates and its relationship to the infection may be overlooked. Failure to recognize the underlying infection may have accounted for the high mortality rate of the early reports in neonates. Recent reports indicate the readier recognition and appropriate treatment of the syndrome (Table 1). In adults, the severity of the accompanying sepsis often compromises the prognosis. The pathogenesis of liver involvement during nonhepatic bacterial infections might be related to direct invasion of the parenchyma by the infectious organism or to structural or functional changes caused by circulating toxins. The occurrence of the cholestatic syndrome, even in the absence of bacteremia, and the similarity of its manifestations during infections with different gram-negative bacteria suggest a pathogenetic role for circulating endotoxin. Endotoxin is a complex lipopolysaccharide (LPS) from the outer membrane of the bacterial cell wall.‘” The intrinsic toxicity of the LPS is linked to the lipid moiety (lipid A), while the polysaccharide region (Oantigen) carries the serologic specificity. The lipid A portion has a similar structure among the Enterobacteriaceae, and this could explain the similarity of the biologic effects of endotoxins from different sources. Unfortunately, the lack of a reliable assay for endotoxin in biologic fluids has thus far hampered the research on the pathogenetic role of LPS in human disease. To test the hypothesis that the jaundice associated with gram-negative bacterial infections might be due to the cholestatic effects of endotoxin, we tested the effects of E. coli’” and S. enteritidis” endotoxins on bile flow by the isolated perfused rat liver (IPRL). These studies showed that both endotoxins caused dose-dependent decreases in bile flow and excretion of organic anions (BSP and ICG) (Figure 2). Analysis of the effects of LPS on bile flow by the IPRL in the absence of added bile salts (Figure 3A) and on canalicular bile formation as measured by “C-erythritol clearance and bile salt excretion (Fig. 3B) suggests a selective decrease of the bile salt-independent fraction (BSIF) of bile. The BSIF is generally considered to be regulated by the activity of the membrane-bound Na+, K+-ATPase, which controls the active transport of sodium.“’ Accordingly, the demonstration’” that both endotoxins at the same concentration which inhibited BSIF in the isolated perfused rat liver, exerted a selective dose-dependent inhibition in the Na+, K+ATPase activity of preparations of rat liver plasma membranes enriched with bile canaliculi (Fig. 3C), supported the inference that the cholestatic effect of LPS was mainly in the BSIF. Endotoxins show high affinity for biologic mem-

~‘i_----_____________:. _---- Day Of Illness

??

DUE TO BACTERIAL

and Brown (1962)

et al. (1972)

” Range.

Miller et al. (1976)

Barges

(1971)

et al. (1971)

Ng and Rawstron

Rooney

3

13

12

11

16

VermiIIion

et aI. (1969)

2 10

Miller and Irvine (1969) Seeler and Hahn (1969)

a 9

Kenny et al. (1966) Arthur, and Wilson

(1967)

7

Danks et al. (1965)

14

15

et al. (1964)

5

4

Ref.

Association

Eley et al. (1965)

Fahrlander

(1963)

of Jaundice

Hamilton and Sass-Kortsak

Bernstein

(Year)

Author

Reports

1.

Table

15/15

e/5

6/O

22

4/3

9 10/l

2/2

11/o

16/9

2/3

5/3

13/11

8/l

M/F

Cases

with Nonhepatic

wk

mo

15 yr-27

2 mo-10

2 wk-0

1 wk-3

18 yr-72

yr

mo

wk

wk

yr

2 wk-8 wk 3 wk-8 wk 12 yr Adults 1 wk-8 wk

1 wk-4

35-54

44-80 yr

1 day-3

2 wk-2 mo

Age

Infections

with

2-200 mean 8.7 (mean 6.8)

7-30/5-20”

6-r~O/1-37~

5-24/4-16°

1.5-2.5” 6-48/2-24a

2-39/2-28” 3-6

10-30

3-23/3-150

3-16

3-31/l-15”

12-22/5-t3O

(mg%)

Tot/Dir

Bilirubin

Gram-Negative

cholestasis

cholestasis

Kupffer cell hypcrplasia

Intrahepatic

Intrahepatic cholestasis Kupffer cell hyperplasia

Intrahepatic cholestasis Mild focal cell necrosis Kupffer cell hyperplasia

Intrahepatic

Bile stasis No necrosis Intrahepatic cholestasis E. M. Bile canalicular dilation with loss of microvillin Intrahepatic cholestasis

Bile stasis Mild toxic changes

Liver histology

Bacteria

(11)

S. aureus Paracoion Klebsiella

E. coli P. aeruginosa

Proteus Paracolon E. cob (5) Paracolon E. coli Proteus

E. coli Paracolon Aerobacter E. coli (3) P. aeruginoso (2) Anaerobic streptococcus E. coli (13)

E. coli (8)

E. coli (13) Enterbacteriacae S. aureus E. coli (11) E. coli (3)

E. coli Proteus Bacteroides

E. coli (6) Paracolon (2) P. aeruginoso (1) E. coli (11) Aerobacter (4) E. coli (3) P. oeruginosa

Agent of infection

13

0

0

0

6

2

1

1

11

9

Deaths

JAUNDICE DUE TO BACTERIAL INFECTION

August 1979

A 24r

10

20

30

40

50

60

70

80

90

Time (min)

Figure 2. 19. Effect of E. coli endotoxin on the rate of bile flow in the isolated perfused rat liver. The “reduced perfusate flow” curve refers to experiments in which, after 30 min. the rate of perfusate flow was mechanically reduced by 26% of the initial value. This was done to distinguish between effects of endotoxin per se on bile flow and indirect effects which might have been medi{ated through alteration of perfusate flow. (From: Utili R, et al: Gastroenterology 70:243-253, 1976.) '24 r

“LJio

,

I

I

,

20

30 40 50 Time (min) Figure 2. B. Effect of E. coli endotoxin (O---O) on BSP excretion. (From: Utili R, et al: J Lab Clin Med 89:471-462,1977.)

branes and Shands”’ has suggested that LPS may cause membrane disorganization, which in turn, may trigger some of the biologic effects of LPS. Our observations, in the in vitro models, which have been confirmed by other workers using an in vitro pig liver system,25 and our studies with the neonatal guinea pig’” provide a reasonable explanation for the cholestasis seen dtiring infections with gram-negative bacteria. The higher susceptibility of neonates to this effect of gram-negative bacterial infection may reflect the immaturity of their biliary excretory mechanisms. Neonates have a lower circulating pool and synthetic rate for bile sa1ts27.*8and therefore, a low bile salt-dependent bile flow. In this setting, the effects of LPS, which selectively inhibits the BSIF, would be enhanced and could result in a cholestatic syndrome.29 Dr. Zimmerman: This series of studies provides an interesting and credible basis for the jaundice asso-

365

ciated with E. coli and some other gram-negative bacterial infections. A classical gram-negative bacterial infection, typhoid fever, has long been known to lead to liver damage. How does it compare with the cholestatic injury of E. coli infections? Dr. LJtiJi: Although now rare in the U.S., typhoid fever continues to occur in other parts of the world. It can induce liver injury which may resemble or differ slightly from that associated with E. coli infections. Jaundice is usually not the only manifestation of hepatic injury or disease, for it is often accompanied by histologic evidence of hepatocellular damage.30-34Recently we studied a patient at the Clinic of Infectious Disease, 1st Medical School of the University of Naples, Italy. A 57-year-old woman was admitted to the hospital with a high fever. Twelve days before hospitalization, she developed fever, shaking chills, vomiting, and headache. The fever continued for a few days reaching 39-40°C each evening. The day before admission she noticed dark urine. On admission the fever was 39.5’C, the pulse was 100, and the blood pressure 105/65 mm Hg. Body weight was 70 Kg. On examination she was found to be jaundiced with a palpable liver at 2 cm below the costal border and a palpable spleen at 3 cm. Urine was dark with bilirubin and urobilinogen strongly positive and slight albuminuria. Total serum bilirubin level was 3.8 mg per dl with 2.3 mg direct-reacting; SGOT was 85 IU and SGPT 41 IU; alkaline phosphatase was 84 IU (normal 20-45). Hemogram showed: RBC-3,000,000; WBC-2,000 with 70 neutrophils, 2 eosinophils, 20 lymphocytes, 8 monocytes; and platelets 90,000. ESR was 18 mm at 1 hr, albumin 2.5 g, and globulin 2.9 per dl. HBsAg was negative. A blood culture grew Salmonella typhi. Treatment with ampicillin (6 g/day) and oral amoxicillin (3 g/day) and a short course of prednisone led to rapid decline of the fever which disappeared by the 5th day. After 1 wk, laboratory values were: serum bilirubin-normal; SGOT-48, and SGPT--44 IU; and alkaline phosphatase-70 IU. RBC-3,600,000; WBC-3,600; and platelets120,000. An oral cholecystogram after 15 days showed a normal gallbladder. She was discharged from the hospital after 23 days with the liver not palpable and the bilirubin level normal. Levels of transaminases and alkaline phosphatase were still slightly elevated. Typhoid hepatitis is characterized by hepatomegaly, jaundice, moderate elevation of alkaline phosphatase and serum transaminases, and a histologic picture of nonspecific reactive hepatitis with mild cholestasis.3”-s4 A review of the literature indicates that jaundice (bilirubin usually below 10 mg per dl) occurs in 4-16% of reported cases.30.“1 Hyper-

366

A

ZIMMERMAN

GASTROENTEROLOGY

ET AL.

1.4---

i 1.2-

cnNlRoLl6) ENDOTOXIN lmg% 161

4 M 7;

1.0-

01

’

10

’

20

’

30

’

’

40

’

50

’

60

’

70

’

80

90

Time (min.)

0.8 10

20

30

40

50

Bile Salt Excretion

Figure

60 @moles.

I

I

I

70

80

90

mine’

. g Liver-‘)

I

IJ

100 110 120

3. A. Effect of E. coli endotoxin on bile flow during perfusion of the isolated rat liver without infusion of taurochoclate, thus representing mainly an effect on BSIF. (From: Utili R, et al: J Lab Clin Med 89:471-582.1977.) B. Relationship between “‘C-erythritol clearance (y-axis) and bile salt excretion (x-axis) before and after addition of E. coli endotoxin. Regression lines were calculated by the least-squares method with r = 0.98 for both lines (P c 0.001).The equations for the lines are y = 1.04 + 0.0072~ before and y = 0.89 + 0.0066x after the addition of the endotoxin. The difference in their slopes is not significant, but their intercepts on the y axis are different (P < 0.001) as calculated by analysis of covariance. The difference in the intercepts represents the effect of endotoxin on BSIF. (From: Utili R, et al: J Lab Clin Med 89:471-482, 1977.) C. Note depression of Na+, K+-ATPase of canalicular-enriched plasma membranes by increasing concentrations of endotoxin (LPS) of E. coli (O-0) and S. enteritidis (u). Other membrane enzymes (Mg++- ATPase, Cl and m S-nucleotidase, A and A) were not inhibited by either endotoxin. (From Utili R, et al: J Infect Dis 138:583, 1977.)

Vol. 77, No. 2

bilirubinemia (values above 1.5 mg per dl), however, has been found in over 25% of cases in whom it was estimated.32 Transaminases are usually less than five-fold elevated but occasionally are markedly elevated. Alkaline phosphatase values are usually two to three times the normal. Jaundice is of short duration and usually disappears before normalization of liver enzymes. Hepatic histology shows focal cell necrosis with mononuclear cell infiltration and marked Kupffer cell hyperplasia (typhoid nodule, Figure 4) together with mild cholestasis.“‘-“4 An electron microscope study has revealed enlarged endoplasmic reticulum with altered mitochondria and dilation of bile canaliculi with loss of microvilli.“’ A follow-up of liver biopsies in 13 cases showed complete resolution in 2 wk in all the cases which had been controlled by therapy.“’ A pathogenetic role of S. typhi endotoxin in the liver damage warrants consideration. However, the effect of the endotoxin of S. typhi appears to differ from that of E. coli or S. enteriditis. Indeed, light and electron microscopic study of rabbits injected with S. typhi endotoxin showed focal areas of liver cell necrosis surrounded by mononuclear phagocytes and hyperplastic Kupffer cells filled with debris.““,36 These lesions were remarkably similar to those found in patients with typhoid hepatitis; whereas E. coli endotoxin leads to cholestasis, and patients with the cholestasis of E. coli infections show an almost normal hepatic parenchyma. Dr. Zimmerman: The foregoing discussion has focused on the jaundice that may accompany nonbacteremic, extrahepatic gram-negative bacterial infection and that which may occur in patients with typhoid fever. The former appears attributable to endotoxemia; it is clearly cholestatic as are the demonstrable effects of E. coli endotoxin in experimental models. We have been told that the jaundice associated with typhoid fever may also be due to endotoxin, but it is accompanied by histologic evidence of hepatocellular injury. Since typhoid fever has a bacteremic phase, the role of blood-borne bacteria in producing hepatocellular injury warrants consideration. Consistent with this suggestion is the observation that infections with E. coli produce jaundice in adults only when there is associated bacteremia. Accordingly, Dr. Hoofnagle will offer an analysis of the effects of generalized sepsis on the liver. Jaundice DR. JAY

in Bacterial

Sepsis

HOOFNAGLE*

Jaundice as a complication of severe bacterial infections in newborns is a well-recognized phe* Formerly Fellow in Gastroenterology, Veterans Administration Medical Center, Washington, D.C.; presently Senior lnvestigator, Liver Unit, National Institutes of Health, Bethesda, Maryland.

August 1979

JAUNDICE DUE TO BACTERIAL INFECTION

Figure 4. Hepatic lesion in typhoid fever. Section from a necropsy liver showing a focus of necrosis with a “granulomatoid” (H & E, x 195). (Courtesy of Dr. Kamal G. Ishak, Armed Forces Institute of Pathology.)

nomenon,‘*4-‘3 but the occurrence of this syndrome in adults has received scant attention. Nevertheless, jaundice as a result of sepsis in the adult has been the subject of several reports.2.3.‘4-‘7 The incidence of such jaundice among one series of 1140 adult bacteremit patients was 0.6%.” No doubt this estimate is low and subclinical liver dysfunction is much more common. Because of problems in studying such patients prospectively the incidence of liver disease resulting from sepsis is not known.’ The jaundice associated with generalized sepsis is also usually cholestatic in nature. It usually appears within a. few days of the onset of bacteremia.z’3 Clinically, tbe liver disease is overshadowed by the symptoms and signs of the systemic infection. Itching and abdominal pain are rare, but hepatomegaly is found in about 50% of cases.3 The peak bilirubin is usually between 5 and 10 mg%, but can be as high as 30-50 m.g%. Most (75-80%) of the bilirubin is directreacting. Serum bile acids are also elevated. The alkaline phosphatase level is abnormal in almost 50% of reported cases, but is rarely more than two to three times elevated.3 The serum transaminases are usually normal but can be elevated slightly (the SGOT in 31% and SGPT in 15% of cases). A summary of laboratory findings as reported in seven recent series on jaundice associated with sepsis is shown in Figure 5. These abnormalities generally resolve promptly with resolution of the bacterial infection. Other tests of hepatic function are usually normal

367

appearance

or minimally decreased. Albumin levels can be low, but are probably no lower than with nonjaundiced episodes of sepsis. The prothrombin time is normal or is correctable with vitamin K therapy. The liver histology found with jaundice associated with bacteremia has been reported by several authors. 3~14-17~37 Most prominent has been the presence of intrahepatic cholestasis with little (focal) or no hepatocyte necrosis. Less commonly, Kupffer cell hyperplasia, nonspecific hepatitis, a slight increase in lymphocytes in portal areas and a mild fatty vacuolization have been described. Bacteremic jaundice has been reported in association with several bacterial organisms, including E. coli, K. pneumonia, P. aeruginosa, H. influenza, various Proteus species, Paracolon and Bacteroides species, aerobic and anaerobic streptococci, and Staphylococcus aureUS.‘-~.‘+~‘.~’ The sources of infection have included appendicitis, diverticulitis, pyelonephritis, pneumonia, endocarditis, pelvic, subphrenic, lung and soft tissue abSCeSSeS.‘-3.‘4-‘7.37 In many of the reported cases, bacteremia has been inferred, but not demonstrated. The diagnosis of jaundice due to bacteremia should be considered in the septic patient who develops hyperbilirubinemia with normal or near normal serum enzymes. Indeed, the sudden onset of jaundice with high fever should suggest the diagnosis of sepsis. This condition frequently appears in the individual with other possible causes for jaundice-in the postoperative period, after multiple blood transfusions, after periods of shock or anoxia,

368

ZIMMERMAN

ET AL.

GASTROENTEROLOGY

9-

8765432-

Jaundice

lBilirubin 153) Figure

5.

77, No. 2

duce intrahepatic cholestasis or parenchymal injury.“.” Dr. Zimmerman: Another classical clinical syndrome is the jaundice associated with bacterial pneumonia. Described one-and-one-half centuries ago, it has had little attention in recent years. Dr. Seeff will describe that entity.

lo-

fi ’ 2 ii! B ;

Vol.

Alkaline Phosphatase 153)

SGOT 1411

SGPT

or while on hepatotoxic drugs. Nevertheless, the constellation of history, physical examination, and laboratory features occurring with bacteremic jaundice are sufficiently characteristic to separate this entity from other causes of jaundice. Liver biopsy is rarely necessary. Perhaps the major differential diagnosis is between liver disease from generalized sepsis and that due to an infection involving the liver-cholangitis or liver abscess. Neale et a1.37have reported that jaundice as a result of “intrahepatic infection” can be separated from that due to generalized or “extrahepatic infection” by serum B,, levels (which were elevated in 4/4 patients with liver abscess or portal pyelophlebitis but which were normal in 6/6 patients with liver disease due to systemic infection). Other data supporting this suggestion, however, are wanting. While the jaundice associated with sepsis denotes severe infection, the hepatic injury contributes little to the morbidity or mortality of the infection. Published series have reported a high mortality rate (as high as 90%),” but this high rate does not reflect hepatic failure and does not correlate with the height or duration of hyperbilirubinemia.” The liver disease itself requires no therapy. Indeed, this form of jaundice should be recognized for what it represents and not lead to unnecessary medical or surgical efforts. The cause of the jaundice associated with sepsis is not known. While some cases of this syndrome may be caused by circulating endotoxin, not all cases are associated with bacterial organisms that produce endotoxin. Other bacterial toxic products, distinct from known endotoxins or exotoxins, may be causative. They may, when present in the circulation, in-

Pneumonia

DR. LEONARD SEEFF’

181

Mean height of serum bilirubin, alkaline phosphatase serum glutamic oxaloacetic transaminase @GOT), and serum glutamic pyruvate transaminase (SGPT) in 53 :ases of jaundice associated with sepsis from six recent :eports.Z.3~5~‘4-‘B~37 The total number of cases for which :ach test was reported is given in parenthesis. (Modiied from Miller et al., reference 2).

in Bacterial

An association between clinical jaundice and lobar pneumonia was first noted in 1836 by Garvin.38 The relationship was observed again by several European physicians at the turn of the century,38-43 and also during the first half of this century by a number of American investigators.“+” In 1950, Zimmerman and Thomas reported on the liver findings in 94 cases of pneumococcal pneumonia, and presented an analysis of data available to that time.” This report was the last to come from a western country, all subsequent ones having emanated either from Africa5z-Boor the Pacific.“’ The original hepatologic abnormality noted in patients with pneumonia was the presence of overt icterus,38-41 no other useful tests being available at the time to permit determination of more specific liver impairment. Representative rates for jaundice in lobar pneumonia are shown in Table 2. There has been a sparsity of recent reports of jaundice in patients with pneumonia from western countries. The decrease has been ascribed to the advent of antibiotics,” but this concept has been challenged.” Nevertheless, it is conceivable that the continued finding of jaundice in African patients may reflect institution of treatment later in the course of their disease than in that of their western counterparts. This factor might also account for the apparent change in the racial distribution of this phenomenon over the many years since its recognition. The earliest published reports of jaundice in pneumonia, which derived from the U.S.A. and Europe, involved mainly Caucasian patients.3”” The publications of the past 46 years have described jaundice in pneumonia as affecting black patients almost exclusively (Table 2). Also of note, as can be seen from the Table, is the apparent rarity of jaundice in females with lobar pneumonia. The reason for these seeming predilections is not known, although several explanations have been offered. One suggestion for the Chief, Gastroenterology/Hepatology Section Medical Service, Veterans Administration Medical Center: Associate Professor of Medicine, Georgetown University School of Medicine, Washington, D.C. ??

JAUNDICE

August 1979

Table 2. Reported Prevalence of Jaundice

in Patients

with

Lobar

Ref.

Frequency

King, cited by Klemperer (1933) Rosenbluth and Block (1937) Curphey and Soloman (1936) Gelfand and Lewis (1942) Turner et al. (1943) Zimmerman and Thomas (1950) Radford et al. (1967)

47 48 49 52 50 51 61

6.6% 23.5% 29.9% 16.0% 67.7% 13.9% 46.6%

Tugswell and Williams (1977)

60 53 54 55 56

22.4% 11 cases 21 cases 6 cases 41 cases

Author (Year)

Hall and parry (1963) Kibukamosoke et al. (1964) Clain and Gelfand (1967) Mekel et al. (1966)

DUE TO BACTERIAL

INFECTION

369

Pneumonia Sex distribution

NS 9O%M NS NS 100% M 9O%M 65% M 1OOM

91 M 100% M 100% M 95%

M

Racial distribution

Geographical area

100% B 100% B lOO%B

USA USA USA Rhodesia USA USA Papua & New Guinea Nigeria Nigeria Uganda

100% B l(XX&B

Rhodesia S. Africa

NS NS NS 100% B 100% B 9O%B lOO%P&NG

NS = not stated: M = male; B = black; P & NG = Papua % New Guinea.

possible greater frequency of jaundice in blacks putatively leading to splinting of the right diawith pneumonia is the presumption that malnutriphragm and hence to obstruction to biliary flow. tion contributes to its development,W53 a suggestion Added to this was the early report of autopsy findings of anatomic changes in bile ducts,q and, more supported by experimental studies showing the development of jaundice in poorly nourished dogs in recently, the prominent cholestasis seen on perwhom pneumonia had been induced.” Recent pubcutaneous liver biopsy.‘4+‘.54 However, many of these lications from Africa and the Pacific, however, tend findings have been challenged, and biochemical tests do not support this view51-53@$and the notion of bilito discount malnutrition as a contributing factor.wsl ary tree obstruction has long been abandoned. More recently the susceptibility of black males has been attributed to the high frequency of glucose-6Most investigators, however, believe that the jaunphosphate dehydrogenase (G-6PD) deficiency among dice is mainly hepatocellular.~-~~51-s3~s’~E* AbnormalthemaO (genetically transmitted as a sex-linked trait), ities suggestive of hepatocellular damage (bromoleading to hemolysis because of the pneumococcal sulfophthalein dye clearance, . thymol turbidity, cephalin flocculation, and the serum transaminases) infection, and the production of hemolysic-induced have been noted in a high proportion of patients jaundice. However, hemolysis as a cause for jaundice, suggested previously by others,B0.82has been rewith pneumonia, with and without jaundice.49~51*BO*s1 jected by most investigators.+‘*45*“‘51Indeed, in some Furthermore, in those with jaundice, all have had increased amounts of direct-reacting bilirubin in the parts of Africa, a correlation between G6PD defiblood and, concomitantly, bilirubin and urobilinociency and jaundice with lobar pneumonia has not been discernible.” gen in the urine.‘l Also, some bilirubin values reOlder than the concept of genetically determined ported have been much higher than is generally seen in hemolysis. For example, although the mean serum hemolysis as a cause of jaundice, has been the asbilirubin value in the study reported by Tugswell et sumption that hemolysis of red cells in the “hepaal. was 4.2 mg/dl, the values in some patients have tized” lung was responsible. Indeed, an experiment been much higher, even as high as 19.0 mg/dl.“~“~“’ in which an increase in serum bilirubin developed All of these phenomena are consistent with findings after intratracheal placement of blood was reseen in intrinsic hepatocellular disease, and permit ported’3 but not confirmed.” Also in support of this designation of the jaundice as being of hepatocelluview has been the findings of an associated rapidly lar origin; although any hemolysis which does occur, increased fecal excretion of developing anemia? would, of course, increase the depth of jaundice. indirect hyperbilirubemia,” and heurobilinogen,” The findings on liver biopsy have also tended to mosiderosis in the lung and liver.Bo Nevertheless, disupport the concept of hepatocellular injury. The rect hyperbilirubinemia and bilirubinemia has made changes on light microscopy have usually been nonit clear that the jaundice is not solely due to hemospecific, but have included cloudy swelling of helysis. An early and naive theory proposed that the patocytes, occasional foci of necrosis, and patchy jaundice was obstructive in origin.40 This derived areas of pleomorphic liver cells53-“5; some investifrom the apparent high incidence of jaundice when the pneumonia involved the right lower lobe,53*80tB’ gators have reported findings suggestive of viral

370

ZIMMERMAN

ET AL.

hepatitis.54,61 Cholestasis has been noted by several observers.14.54.57In support of their concept of hemolysis as the primary mechanism of jaundice, however, Tugswell et al. reported finding excess ironcontaining pigment in the liver by light microscopy, and erythrophagocytosis by Kupffer cells on electron microscopy.” Also, the lysosomes in the Kupffer cells were noted to contain ferritin, a change consistent with excessive hemolysis. This is in contrast to the ultrastructural changes noted by Theron et a1.57They found dilation of the bile canaliculi with a decrease in the size and number of microvilli, and pericanalicular intracytoplasmic vacuoles. In addition, hepatocellular bile-deposits were regularly seen, although canalicular bile plugs were rarely encountered. Also noted was an increased number of “lipocytes” in the space of Disse. The authors of that report suggested that these ultrastructural abnormalities, when taken together, were consistent with transient toxic liver injury, with marked cholestasis. The specific cause for the hepatic impairment in lobar pneumonia is unknown, but has variously been related to the virulence of the infecting organism,48.49the presence of fever,03@’anoxia,45~4sor toxemia.44.5s.61With regard to the former, almost all reports have involved illness caused by Dipiococcus pneumoniae. However, reports of jaundice developing in patients with Klebsiella pneumoniae and other organisms have appeared.” Attempts to correlate the development of jaundice with the pneumococcal serotype have, by and large, been unrewarding, although in one study, jaundice appeared to be most common with type II,4g and in another, with type V pneumococcal infection.‘” The development of jaundice, however, does not seem to correlate with a poor prognosis.5’.53.54.58.80.61 Although jaundice is known to be produced by high fevers3.ss available evidence would suggest that this is not the cause in patients with pneumonia. In the study of Zimmerman and Thomas,‘l there was no correlation between the intensity and frequency of liver impairment and the height of the fever. Also, Harrir? has shown that liver dysfunction is less common in patients with most other febrile illnesses. Anoxia, suggested by others to be of importance45.46did not appear in the study of Zimmerman and Thorna? to play a key role. Indeed, in that study, the most important determinant for the development of liver dysfunction and jaundice was the degree of alcoholism which preceded the admission. However, it must be remembered that alcoholics may develop lobar pneumonia and, concomitantly, acute alcoholic hepatitis. Finally, a direct toxic effect of organisms, or an exo- or endotoxin, might be the primary precipitant of liver dysfunction, but this remains to be demonstrated.

GASTROENTEROLOGY

Vol. 77, No. 2

Dr. Zimmerman: This conference has offered a glance at some nonhepatic conditions that may simulate hepatic disease. We considered the effort to be worthwhile for students of disease as an expansion of the spectrum of hepatology and useful for clinicians whose most important problem continues to be accurate diagnosis for the direction of appropriate therapy. The examples chosen to help us focus on the problem include those of regular clinical importance, i.e., gram-negative bacterial infection as the cause of cholestatic jaundice as well as problems of classical interest in medicine, i.e., typhoid fever, pneumococcal pneumonia, or sepsis as the cause of jaundice. The list of bacterial infections that can lead to jaundice can be extended, of course, (Table 3) and now even includes the newly recognized Legionnaire’s disease.m Two characteristics of the hepatic involvement of these infections warrant emphasis. The hepatic involvement of most of these conditions adds no additional threat to that of the underlying disease. Furthermore, jaundice of pneumonia or sepsis, the cholestasis associated with gram-negative bacterial infections, the “hepatitis” associated with secondary syphilis, the perihepatitis that accompanies gonococcal peritonitis in the female, each may serve to draw attention to the underlying infection, and so lead to appropriate antimicrobial therapy. This is the uncommon circumstance, however. Most instances of these infections are recognized as such, and jaundice is usually absent. When present it will be recognized as a complication of the underlying infection only if its likelihood to occur is known. The hepatic involvement of a number of systemic viral illnesses’.B’-‘og is listed in Table 4. It differs from that of the bacterial infections with regard to both of the cited characteristics. The hepatic injury per se may add a threat to survival beyond that of the systemic illness; and, of course, recognition of the underlying infection is of no practical help in therapy. Severe hepatic injury may be caused by Herpes simplex infection in the neonatal, pregnant or compromised host,81-ARby the Marburg virus,“” by yellow fever,lm and even by infectious mononucleosis.‘M Rubella in the neonate can lead to chronic hepatic disease and even to cirrhosis.1.10Z.103Until specific therapy of viral disease becomes more effective, the signalling of systemic viral infection by its hepatic involvement is of interest but of only limited practical use. Protozoan disease also can produce jaundice. Toxoplasmosis in adults leads to a syndrome resembling infectious mononucleosis.’ Rarely it may include jaundice. Malaria leads to jaundice, which would seem mainly attributable to hemolysis. It also can lead to hepatic parenchymal injury, however, which

August

1979

Table

3.

Type

JAUNDICE

Nonhepatic

of infection

Bacterial

Infections

Type

Coccal Pneumococcal Streptococcal (B. hemol.) Staphyloccal sepsis Gonococcal perihepatitis

or CH

Ch

ChRrFN

Ch

Ch&FN

H-Cell

Tuberculosis

H-Cell CH

Spirochetal Leptospirosis

Syphilis Relapsing ‘I H-Cell lshak.

fever

= Hepatocellular;

Rarer than in past Especially in scarlet Very rare of subcapsular

FN; typhoid nodule Granulomatous & diffuse hepatitis FN ?

In women

Relatively frequent lesion Hepatic involvement frequent: jaundice Jaundice rare

1

1. 71, 72

Invasion of liver by organisms presumably contributes to severity Jaundice is very rare

1 1

1

necrosis Very rare

lcterogenesis varies with strain of organism. In USA L. icterohemorrhagico 6 L.

b FN = Focal

Table

rare

CH; FN; Cellicular degeneration, inflammation

CH = Cholestatic.

1

30-35

H-Cell-CH

FN

Table

uncommon

Jaundice

H-Cell

2

69,70

with gc peritonitis

FN; periportal microvesicular steatosis”

Hepatitis

Table 65,66 67,68

fever

H-Cell

H-Cell

371

Ref.

Causes jaundice mainly in neonates. Important cause of infaniile jaundice Can cause jaundice at any

Granulomas & caseous Tuberculous cholangitis

INFECTION

Comment

age, relatively

H-Cell Hemolytic

disease

BACTERIAL

to Jaundice

FN FN ? Hepatitis areas

Tularemia Clostridia

Legionnaire’s

Lead

Lesionb

H-Cell

H-Cell

Brucello!sis

Can

of jaundice”

H-Cell H-Cell H-Cell

Bacillary E. coli & related species as localized extrahepatic infection (es., urinary tract) E. coli & related gramnegative species with bacteremia & sepsis S. typhi (¶typhi

that

DUE TO

like; granulomas

necrosis:

presumably contributes to the jaundice.‘.“‘.“2 African trypanosomiasis can lead to hepatic parenchymal injury and jaundice.l13 Amebiasis, of course, can involve the liver as an abscess, but amebic abscess rarely leads to jaundice.‘14 Distinction of infection which is hepatic from systemic infections involving the liver is, in a sense, arbitrary. However, it is reasonable to consider the infection hepatic when its chief threat is to the liver and the systemic manifestations are clearly of secondary importance. This seems readily appropriate for viral A, B, and “non-A-non-B” hepatitis. When the chief threat of the illness is systemic or extrahepatic, it is reasonable to recognize the hepatic injury as a complication or manifestation of the underlying disease. These are the illnesses listed in Tables 3 and 4. Many factors can contribute to the hepatic involvement in systemic infection. Distortion of he-

is slight

80

canicoia are most likely to cause jaundice. Secondary syphilis neonatal congential syphilis Jaundice in severe disease

CH = only bilirubin

casts.

c Personal

communication

1, 73, 74

1.75-79 1 by Dr. K. G.

patic function and structure can be quite nonspecific as in the hepatic injury of very high feveP or in the possible effects of anoxia, secondary to pulmonary involvement in pneumonia.51 It may be more specifically related to the organism responsible for the extrahepatic infection as in the cholestasis which seems attributable to endotoxin,lY in the hepatic necrosis that may occur in diphtheria and which can be mimicked by the effect of diphtheria exotoxin,l” in the hepatic injury that has accompanied scarlet fever,“’ and which also brings to mind the necrogenie effect of streptococcal exotoxin.m Conceivably, immune responses tn bacterial infections or to virus infection could lead to hepatic lesions, and, of course, actual invasion of the liver by the organisms could be responsible. There is little evidence, however, to support the view that direct invasion of the liver by bacteria is responsible for the hepatic abnormality associated

372

ZIMMERMAN

Table

4.

Agent

ET AL.

GASTROENTEROLOGY

Viral and Rickettsial

Disease that Can Lead to jaundice

or disease

Lesion”

Herpes simplex Cytomegalovirus Adenovirus Rubella Marburg virus Lassa fever & other hemorrhagic Reo Virus Rift Valley fever Chicken pox Yellow fever Echo virus Infectious mononucleosis Mumps Cocksackie B Q fever Rocky mountain spotted fever

fevers

Susceptibles”

Ref.

FN, MN FN, MN FN, AN

N. ImSA, Pr N, ImSA, Post-trans One ImD infant

1,81-88 1,89-100 101

Chronic Hepatitis MN MN FN “Hepatitis” FN

N All exposed All exposed Reported in three infants All exposed Adults with severe generalized All exposed

l, loo-104 105 106 107 108

Fat, MZN ? “Hepatitis” FN “Hepatitis” FN, Gran “Hepatitis”

All All All All All

” FN = focal necrosis; MN = Massive Necrosis; AN = areas of necrosis; nates, ImSA = immunosuppresscd adults; post-trans. = after transfusion;

with

most systemic bacterial disease.’ Bacteria can rarely be isolated from the liver.’ Even in the presence of specific lesions such as the granulomas of hematogenous tuberculosis, organisms are very difficult to isolate. Nevertheless, the possibility that hepatic injury may be a consequence of bacteria reaching the liver, producing hepatic injury and then disappearing, cannot be dismissed.’ It is also worthy of note that the presence of bacteria in the bloodborne hepatic abscess often will not lead to jaundice. Indeed, jaundice in the patient with hepatic abscess is likely to reflect the cholangitic pathogenesis of the abscess.“’ Furthermore, rare instances of bacteria isolated by liver biopsy from patients with febrile illness but no clinical evidence of hepatic disease have been reported.“”

Concluding

Vol. 77. No.2

Comments

The goal of this exercise has been to draw attention to a group of syndromes which are not ordinarily considered to belong to the universe of hepatic disease, but which may mimic or lead to hepatic disease. Awareness of hepatic involvement in systemic and extrahepatic conditions is of practical and hypothetical importance. It expands the spectrum of hepatic disease, permitting more precise diagnosis. It may be of help in selecting therapy. It may improve the understanding of mechanisms of hepatic injury. There are many other facets of the interface between infection and the liver which are beyond the scope of this discussion.

References 1. Klatskin G: Hepatitis associated with systemic infection. Edited by L Schiff. In: Diseases of the Liver. 4th edition, Philadelphia, Lippincott, 1975, p 711-754 2. Miller DF, Irvine RW: Jaundice in acute appendicitis. Lancet 1:321-323,1969

exposed exposed exposed exposed exposed

especially

N

disease 104 1,104 1,109 1. 104 110

MZN = midzonal necrosis; and Gran = granulomas. pr = pregnant; and ImD = Immune deficient.

” N = Neo-

BJ: Jaundice in 3. Miller rJJ, Keeton GR, Webber BL, Saunders severe bacterial infection. Gastroenterology 71:94-97,1976 4. Bernstein J, Brown AK: Sepsis and jaundice in early infancy. Pediatrics 29:873-882, 1962 JR, Sass-Kortsak A: Jaundice associated with se5. Hamilton vere bacterial infection in young infants. J Pediatr 63:121132,1963 MB, Barton LL. Marshall RE, et al: The frequency 6. Escobedo of jaundice in neonatal bacteria1 infections. Clin Pediatr 13:656-657.1974 PE, Connelly JF: An etiology study of 7. Danks DM, Campbell neonatal jaundice in a childrens’ hospital. Aust Paediatr J 11:193-201.1965 DN, Kleyn S, et al: An outbreak of uri8. Kenny JF, Medearis nary tract infections and septicemia due to Escherichia coli in male infants. J Pediatr 68:530-541,1966 infection presenting with 9. Arthur AB, Wilson BDR: Urinary jaundice. Br Med J 1:539-540,1967 tract infection in in10. Seeler RA, Hahn K: Jaundice in urinary fancy. Am J Dis Child 118:553-558, 1969 with bac11. Rooney JC. Hill DJ, Danks DM: Jaundice associated terial infection in the newborn. Am J Dis Child 122:39-41, 1971 JR: Urinary tract infections presenting 12.. Ng SH, Rawstron with jaundice. Arch Dis Child 46:173-176,197l manifcsta13. Borges MAG, DeBrito T, Borges JMG: Hepatic tions in bacterial infections of infants and children. Clinical features, biochemical data and morphologic hepatic changes (histological and ultrastructural). Acta Hepato Gastroenterol 19:328-344,197Z H, Huber F, Gloor F: lntrahcpatic retention of 14. Fahrlander bile in severe bacteria1 infections. Gastroenterology 47:590599,1964 15. Eley DF. Hargreaves T, Lambert HP: Jaundice in severe infections. Br Med J 2:75-77, 1965 SE, Gregg JA, Baggenstoss AH, et al: Jaundice as16. Vermilion sociated with bacteremia. Arch Intern Med 124:611-618, 1969 17. Monges A, Tronconia JC, Legre M, et al: L’lctere satellite des infections urinaires gravidiques. Med Chir Dig 2:343-350, 1973. 18. Ludcritz 0, Galanos C, Lehmann V, et al: Lipid A: chemical structure and biological activity. J Infect Dis 128:17-29, 1973

August

1979

19. Utili R, Abernathy CO, Zimmerman HJ: Cholestatic effects of Escherichia coli endotoxin on the isolated perfused rat liver. Gastroenterology 70:248-253,1978 20. Utili R, Abernathy CO, Zimmerman HJ: Effects of Salmonella enteritidis endotoxin on the excretory function of the isolated perfused rat liver. Proc Sot Exp Biol Med 155:184188,3977 21. Utili R, Abernathy CO, Zimmerman HJ: Studies on the effects of E. coli endotoxin on canalicular bile formation in the isolated perfused rat liver. J Lab Clin Med 89:471-482,1977 22. Bayer JL, Reno P: Properties of (Na+, K+)-activated ATPase in rat liver plasma membranes enriched with bile canaliculi. Biochim Biophys Acta 401:59-72,197s 23. Utili R, Abernathy CO, Zimmerman HJ: Inhibition of Na+, K+-ATPase by endotoxin: a possible mechanism for endotoxin-induced cholestasis. J Infect Dis 138:583-587,1977 24. Shands JM: Affinity of endotoxin for membranes. J Infect Dis 128:S197-201.1973 25. Rodriguez-Mantes JA, Rossi I, Gutierrez-Noguera M, et al: Action de la endotoxina de1 escherichia coli sobre h&ado de cerdo aislado. Rev Clin Espan 148:127-130.1978 26. Utili R, Abernathy CO, Aron SA, et al: In vivo effects of Escherichia coli endotoxin on sulfobromophthalein clearance in the guinea pig. Experientia 33:1631-1632.1977 27. Watkins JB, Ingall D, Szczepanik P, et al: Bile-salt metabolism in the newborn. Measurement of pool size and synthesis by stable isotype technic. N Engl J Med 288:431-434, 1973 28. Watkins JB, Szczepanik P. Gould JB, et al: Bile-salt metabolism in the human premature infant. Preliminary observations of pool size and synthesis rat following prenatal administration of dexamethasone and phenobarbital. 69:706-713.1975 Gastroenterology 29. Utili R, Abernathy CO, Zimmerman HJ: Endotoxin effects on the liver. Life Sci 20:553-568,1977 30. Stuart BM, Pullen RL: Typhoid, clinical analysis of threehundred and sixty cases. Arch Intern Med 78:629-661,1946 33. DeBrito T, Trench-Vieira W, Diagostino-Dias M: Jaundice in typhoid hepatitis. A light and electron microscopy study based on liver biopsies. Acta Hepato-Gastroenterol 24:426433, ‘1977 32. Ramachandran S, Godfrey JJ, Perera MVF: Typhoid hepatitis. JAMA 230:236-240, 1974 33. Mallory FB: A histological study of typhoid fever. J Exp Med 3:139-151,197s 34. Ridaura-Sanz C: Patologic hepatica en fiebre tifoidea. Patologia 13:139-151,1975 35. Morgan HR: Pathological changes produced in rabbits by a toxic sometic antigen derived from Eberthella typhosa. Am J Path01 19:135-145,1943 36. Schwartz A, Rubinstein HS, Coons AH: Electron microscopy of cellular responses following immunization with endotoxin. Am J Path01 53:331-353.1968 37. Neale G. Caughey DE, Mollin DL, Booth CC: Effects of intrahepatic and extrahepatic infection on liver function. Br Med J 1:382-387, 1966 38. Garvin IP: Remarks on pneumonia biliosa. South Med Surg 1:536-544, 1836 39. Banti G: Ueber der Entstehung der Gelbsucht bei Pneumonitis. Centralbl f Bakt 20:849-853.1896 40. Abra,mow S: Beitrage zur Pathogenese des Icterus. Virchows Arch f Path Anat Physiol Klin Med 181:201-276.1905 41. Ardin-Delteil M: Pneumonie avec ictere; liepatite et angiocholite pneumococciques. La Tribune Med Paris 42:168169,1909 42. Bittorf A: Die Pathogenese der biliosen Pneumonie. Deuisches Arch f Klin Med 126:474-484.1918

IAUNDICE

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373

43. Maugeri S: Die pulmonogene Entstehung des Ikterus. Beitrag zur Kenntnis der extrahepatischen Bilirubinbildung. Beitr Z Path Anat U.Z. Allg Path 86:375-386,193l 44. Harris BR: Alterations in liver function as an index of toxemia in pneumococcus lobar pneumonia. J Clin Invest 4:211224.1927 45. Elton NW: Icterus index in lobar pneumonia. N Engl J Med 201:611-617.1929 46. Rich AR: Pathogenesis of forms of jaundice. Bull Johns Hopkins Hosp 47:338-377.1930 47. Klemperer P: Pathology of Icterus. NY State J Med 33:13091316,193O 48. Rosenbluth MB, Block M: Pneumonia due to type V pneumonococcus. Arch Intern Med 60:567-573,1937 49. Curphey TJ, Soloman S: Studies in liver function in pneumonoccal pneumonia. Am J Med Sci 196:348-359.1938 50. Turner EL, Bent MJ, Holloway GD. et al: Nutritional deficiency as an etiological factor in icterus accompanying pneumonia in the Negro. South Med J 36:603-608,1943 51. Zimmerman HJ, Thomas LJ: The liver in pneumonoccal pneumonia: observations in 94 cases on liver function and jaundice in pneumonia. J Lab Clin Med 35:556-567,195O 52. Gelfand M, Lewis B: Jaundice associated with pneumonia in natives of Mashonaland. S Afr Med J 16:436-439,1942 53. Hall EW, Parry EHO: Lobar pneumonia with jaundice in adult Nigerians. Trans Roy Sot Trap Med Hyg 57:206-212. 1963 54. Kibokamusoke JW, Pate1 KM, Hutt MSR: Liver biopsy studies in jaundice associated with lobar pneumonia. East Afr Med J 41:203-310,1964 55. Clain D, Gelfand M: Jaundice and pneumonia in the Africian. Cent Afr J Med 10:217-220,1964 56. Mekel RCPM;Theron JJ, Simson IW: Pneumonia with jaundice in the Bantu. Proceeding of the Third World Congress of Gastroenterology 3:283,1967. 57. Theron JJ. Pepler WJ. Mekel RCPM: Ultrastructure of the liver in Bantu patients with pneumonia and jaundice. J Path 106:113-117.1972 58. Parent MA: G-6 PD deficiency in jaundice associated with lobar pneumonia. Lancet 2:155. 1973 59. Owusu SK: G-6 PD deficiency in jaundice associated with lobar pneumonia. Lancet 2:325-326,1973 60. Tugswell P, Williams 0: Jaundice associated with lobar pneumonia. Q J Med 66:97-118,1977 61. Radford AJ, Rhodes FA, Matz LR: The association of jaundice with lobar pneumonia in the territory of Papua and New Guinea. Med J Austr 2:678-681.1967 62. Chierici A: The nature of icterus in lobar pneumonia. Riforma Med 48:1944-1946,1932 63. Bragdon JH: The hepatitis of hyperthermia. N Engl J Med 237:765-769,1947 64. Herman RH, Sullivan BH, Jr: Heatstroke and jaundice. Am J Med 27:154-166.1959 65. Fishbein WN: Jaundice as an early manifestation of scarlet fever: report of 3 cases in adults and review of the literature. Ann Intern Med 57:60-72.1962 66. Ginsburg I, Gallis HA, Cole RM, et al: Group A streptococci: localization in rabbits and guinea pigs following tissue injury. Science 166:1161-1163,1969 67. Bingold K: Uber septischen Ikterus. Z Klin Med 92:140-159. 1921 68. Skinner D, Keefer CS: Significance of bacteremia caused by Staphylococcus aureus: a study of one-hundred and twentytwo cases and a review of the literature concerned with experimental infection in animals. Arch Intern Med 68:851875,1941 69. Stanley MM: Gonococcic peritonitis of the upper part of the

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abdomen in young women. Arch Intern Med 78:1-13.1946 perihepatitis: report of 70. Vickers FN. Maloney PJ: Gonococcal 3 cases with comments on diagnosis and treatment. Arch Intern Med 114:120-123,1964 NB, Eisele CW: Brucella hepatitis leading to cir71. McCullough rhosis of the liver. Arch Intern Med 88:793-802,1951 PJ, Martin WJ, Merritt WA, et al: Brucellosis: re72. Osmundson port of an unusual case. Proc Staff Meet Mayo Clin 32:58-t%, 1957 AD, Galton MM: Leptospirosis in 73. Heath CW, Jr, Alexander the United States. Analysis of 483 cases in man (1949-1961). N Engl J Med 273:857-864,1965 Edited by CH Binford. 74. Dooley JR, Ishak KG: Leptospirosis. DH Connor. In: Pathology of Tropical and Extraordinary Diseases: An Atlas. Vol. 1. Washington, D.C., Armed Forces Institute of Pathology. 1971. p lot-105 75. Baker AL, Kaplan MM, Wolfe HJ. et al: Liver disease associated with early syphilis. N Engl J Med 284:1422-1425.1971 (early) syphilis. N Engl J 76. Sherlock S: The liver in secondary Med 284:1437-1438.1971 reaction 77. Young E, Bahr G, Waye JD: The Jarisch-Herxheimer in syphilitic hepatitis. Am J Gastroenterol61:476-477, 1974 GF, Conn HO: Liver disease associated 78. Lee RV, Thornton with secondary syphilis. N Engl J Med 284:1423-1425,197l syndrome and 79. Bansal RC, Cohn H, Fani K, et al: Nephrotic granulomatous hepatitis in secondary syphilis. Arch Dermato1 114:1228-1229,1978 KM, Meyer RD: Legionnaire’s disease: 80. Kirby BD, Snyder clinical features of 24 cases. Ann Intern Med 89297-309, 1978 ES III, Scofield GF: Hepatoadrenal necrosis: fatal 81. Tucker systemic Herpes simplex infection: Review of literature and report of two cases. Arch Path01 71:538-547,196l infection with Herpes simplex virus 82. White JG: Fulminating in premature and newborn infants. N Engl J Med 269:455460.1963 CE, Huffines WD: Primary disseminated Herpes 83. Wheeler simplex of the newborn. JAMA 191:455-460,1965 Br Med J 1:294, 1969 84. Editorial: Herpes hepatitis. H, Stenram U, Tegner KB, et al: Herpes simplex 85. Diderholm hepatitis in an adult. Acta Med Stand 186:151-155,1969 IE: Adult Herpes simplex hepatitis. Human 86. Lee JC, Fortuny Path01 3:277-281,1972 Br Med J 1:248, 1973 87. Editorial: Herpes hepatitis. EM, Hieger LR, et al: Fulminant her88. Goyette RE, Donowho pes virus hominis co1 43:191-196,1974

hepatitis

during

pregnancy.

89. Fisher ER, Davis E: Cytomegalic-inclusion adult. N Engl J Med 258:1036-1040,1958

Obstet disease

Gynein the

E, Kaariainen L: Cytomegalovirus as a possible 90. Klemola cause of a disease resembling infectious mononucleosis. Br Med J 2:1099-1102.1965 JB. Betts RF, Simon G, et al: Acquired cyto91. Henshaw megalovirus infection. Association with hepatomegaly and abnormal liver function tests. N Engl J Med 272:602-609, 1965 92. Lamb SG, Stern H: Cytomegalovirus mononucleosis jaundice as presenting sign. Lancet 3:1003-1006,1966 93. Carter AR: Cytomegalovirus Br Med J 3:786,1968

disease

presenting

with

as hepatitis.

94. Henson D: Cytomegalovirus hepatitis in an adult. topsy report. Arch Path01 88:199-203,1969

An au-

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