Jaundice after Renal Allotransplantation MARTIN F. MOZES, M.D., NANCY L. ASCHER, M.D., HENRY H. BALFOUR, JR., M.D., PH.D., RICHARD L. SIMMONS, M.D., JOHN S. NAJARIAN, M.D.
Of 567 patients receiving renal transplantation at the University of Minnesota between October 1%7 and October 1975, 22 developed clinical jaundice. Of these 22, nine died with their initial episode of hepatitis, six died within three months of causes associated with liver malfunction, four developed evidence of chronic hepatic failure and only three totally recovered from their illness. Five had clear evidence of Australia antigen positive hepatitis B, four of cytomegalovirus hepatitis, two of herpes hominis hepatitis, one of varicella zoster hepatitis and three of hepatic failure associated with systemic bacterial and/or fungal sepsis. Two of the 22 patients were thought likely to have cytomegalovirus hepatitis though definite proof was absent and in five patients a clear-cut etiology could not be made. In many of these patients the diagnosis was confounded by the previous presence of HB,Ag antigen and the frequent occurrence of a previous or concurrent infection with cytomegalovirus. The role of various drugs including azathioprine, sulfisoxazole, chlorpromazine, acetominophen, etc., could not be established but major roles for these agents in the face of the many viral and bacterial infections present in these patients is doubted. No clear-cut therapy could be established although it appears safe to discontinue azathioprine for longer or shorter periods of time with or without substitution of cyclophosphamide without serious deterioration of renal function. The problem of hepatic failure in transplant patients is still unsolved and will require a prospective study of etiologic agents and sub-clinical hepatic dysfunction in order to establish even the first principles of clinical-pathological correlation.
EPATIC DYSFUNCTION iS seen frequently after re1"4'7'8,14,18,24,30,32'45 The renal transplantation. ported incidence depends on the criteria used to make the diagnosis and varies from 7% (four-fold elevations of transaminases or serum bilirubin greater than 2 mg%))4'718.30 to 67% (two-fold abnormal dye retention).4 Whereas most of these enzyme abnormalities are of indeterminate clinical significance,4 a small per cent of patients progress to frank liver disease and
death. Identification and early institution of therapy in these high risk patients may improve their poor prognosis. The etiologies of liver dysfunction have been attributed to a variety of viral and/or pharmacologic agents Reprint requests: Martin F. Mozes, M.D., Department of Surgery, University of Illinois at the Medical Center, Chicago, Illinois 60680. Submitted for publication: November 12, 1977.
From the Departments of Surgery and Laboratory Medicine/Pathology, University of Minnesota, Minneapolis, Minnesota
for which the evidence is circumstantial. Questions still exist regarding the proper treatment and whether or not immunosuppressive agents4'7'8'34'45 should be changed. This study was designed to review, in a large kidney recipient group from a single medical center, those patients who developed the more severe form of hepatic dysfunction, i.e. those with jaundice. In this group of 22 patients we have attempted to define the mode of clinical presentation, a useful diagnostic approach, etiologic classification and prognostic guidelines. Materials and Methods From October 1967 to October 1975, 567 patients received 661 renal allografts at the University of Minnesota; 271 were from cadaveric donors and 390 from living related donors. The methods of patient selection, techniques of transplantation and methods of immunosuppression have been described elsewhere.37 Twenty-two patients have been identified who developed clinically apparent jaundice at some time during their posttransplant course. Only patients with a serum bilirubin of 2.0 mg% or higher were selected for this study (normal range = 0.1-1.6 mg%). (Patients who demonstrated liver enzyme abnormalities without bilirubin elevation were not included.) All 22 patients were admitted to the hospital at the time of their illness. This patient group was analyzed for the clinical, biochemical, pharmacological, microbiological and histopathological aspects of their illness. All survivors have been followed (27 months to seven years) with regard to longterm survival, kidney graft function and liver function status. Detailed autopsies, including viral and bacterial cultures, were performed on 15 of the 17 patients who died. Particular attention was paid to chemical abnormalities, i.e., blood urea nitrogen (BUN), creatinine, bilirubin, glutamicoxaloacetic transaminase
0003-4932/78/1200/0783 $00.90 C J. B. Lippincott Company
783
784
Ann. Surg. * December 1978
MOZES AND OTHERS TABLE 1. Characteristics oflcteric Transplant Patients
Transplant Number Period (Inclusive)
Total Number of Transplants
Total Number of Patients
Number of Icteric Patients
M:F
Oct. 1967-Oct. 1975
661
567
22 (4%)
11:11
Mean Age* (Range)
LRD:CAD
1st
2nd
34.3
11:11
19
3
(20-53) *
One child age 31/2 years not included. M
=
male. F
=
female. LRD
(SGOT), alkaline phosphatase, lactic-dehydrogenase (LDH) and serum protein electrophoresis. In order to gain prognostic information, liver function studies were noted at the onset of liver dysfunction, as well as the maximal level attained. Microbiological studies included standard aerobic and anaerobic bacterial cultures and fungal cultures. Serology for hepatitis B (HB,Ag) antigen was performed by both counter electrophoresis (CEP) and radioimmunoassay (RIA). Viral serology for complement fixing antibody (CF) against cytomegalovirus (CMV), herpesvirus hominis (HVH) and varicella zoster (VZ) was obtained. Viral cultures for these viruses utilized methods previously described.:8 An antibody titer 1:4 was considered positive and a two-fold rise of titer was considered evidence of recent viral infection. Patients were additionally grouped according to the most likely primary etiology in each case. Results
Clinical Profile and Prognostic Significance of Clinical Facctors
Age and donor source (Table I). Among the 22 patients with clinically apparent jaundice, there were ten adult males and 11 females with a mean age of 36.0 and 32.9 years respectively. There was one male child 3.5-years-old. Nineteen patients had received one kidney transplant and three patients received two transplants. Eleven patients received kidney grafts from living related donors and 11 from cadaveric donors (Table 1) (there is a greater than 4:3 ratio of recipients
=
living related donor. CAD
=
cadaver donor.
of related transplants to recipients of cadaver transplants in our entire series). Time interval, transfusion history, and renal function. In 18 of 22 patients, the duration of dialysis before transplantation was less than six months but all patients received blood transfusions either while on dialysis or in the course of their operations (bilateral nephrectomy and splenectomy and/or transplantation). The time interval between transplantation and the onset of icterus was less than six months in ten of the 22 patients (in six of ten it was less than six weeks, Tables 2-7). In 12 patients, the interval varied from 8-39 months and in one patient it was over eight years. Patients with CMV hepatitis had a shorter interval from transplant to jaundice (see below). With the exception of one patient who developed jaundice shortly after removal of a second rejected graft, almost all of 22 patients became icteric with good renal function (serum creatinine 22
+/
-/
Clin
PM
Clin
PM
-
+
Early
Late/PM
-
-
Bx: cirrhosis PM: massive hepatic necrosis
-
-
ND ND
-
+
2 3
35/F/LRD 41/M/CAD
12 12
+ +
-
+/
+/-/
-/ -/
-
4
21/M/CAD#2
8
+
-
+/-
+/-
+/-
-
ND
-
ND
-
-
PM: coarse nodular cirrhosis & CAH
5
21/F/CAD#2
1:4)
HB,Ag
(Early)
21/F/LRD
7 yrs
-
+
-/
20/F/LDR 19/F/LRD
28 2
-
-
*-+
+
+/+ -/-
++
-
-/-
+
Total # = 3
-
0/3
2/3
1/3
1/3
0/3
Kidney Source
6 7
HVH
Bact. Cultures (Pathogen)
Liver Pathology
TTiter
Months Posttx
Pt #
8
WBC 22
AtJD
PreJD .
Clin .
.
* Significant rise in CMV antibody titer (1:512) two months following illness. JD related donor. CAH = chronic active hepatitis. ND = not done.
.
0/3
=
PM
0/3
Clin
PM
/+ /+ blood liver /+ /1/3
jaundice. Clin
1/3
=
Early
Late/PM
-
-
-
-
-
+
0/3
1/3
clinical. PM
=
Outcome
(Biopsy or PM) PM: submassive hepatic necrosis; H. Hominis ND ND
postmortem. Bx
Death in liver failure; diffuse bleeding Alive and well Alive and well Dead = 1/3 CAH = 0/2
=
biopsy. CAD
=
cadaver donor. LRD
=
living
Ann. Surg. * December 1978
MOZES AND OTHERS
786
TABLE 5a. Cytomegalovirus (CMV) Hepatitis CMV/HVH & VZ Serology Pt #
Age/Sex/ Kidney Source
Months Posttx
HB,Ag
WBC 1:4)
PreJD
AtJD
tTiter >22
Clin
+1-
+1+
-1-
+
Bact. Cultures (Pathogen)
HVH
PM
Clin
PM
Early
Late/PM
+
-
-
+*
-
-
-
-
+
PM: Plasmacell and lymph infiltrate; CMV inclusions Bx & PM: Cholestasis; focal necrosis; CMV inclusions PM: Bile stasis; fatty changes Bx & PM: Massive hepatic necrosis
liver 10
25/M/LRD
I
+
+
-I
-I
-I
11
30/F/LRD
I
-
+
+/+
+/+
+/
-
+
-
-
-
+
12
25/M/LRD
6
-
+
+/
-/
-/
+
+
-
-
-
+
mn = 2.5
1/4
3/4
3/4
2/4
1/4
3/4
4/4
0/4
0/4
1/4
3/4
Total # = 4
+ + liver liver
Liver Pathology (Biopsy or PM)
Outcome Death from bleeding secondary to liver biopsy Death with CMV pneumonia and respiratory failure Death of CMV; respiratory failure Death. Acute hemorrhagic pancreatitis and hepatic failure Death = 4/4
TABLE 5b. Probable Cytomegalovirus (CMV) Hepatitis 23 I
53/M/CAD
13 14
3.5/M/LRD
+ +
-
-
+/
+/+
?*
ND
ND
ND
* CMV antibody titer 1:256, but no recent titer available to confirm donor. m-n = mean. ND = not done.
ND ND
ND
rise. JD = jaundice. Clin
ND ND
ND =
-
+
-
-
Death of liver failure Death. Varicella
ND ND
clinical. PM = postmortem. Bx = biopsy. CAD
=
cadaver donor. LRD
=
living related
l1.5 mg% (Table 2). Renal function remained essentially without change throughout the illness and in all long term survivors. Serum bilirubin. On admission, serum bilirubin ranged from 1.4 to 11.1 mg%. The mean admission bilirubin level was 5.6 mg% in patients who subsequently died (range = 2.5-11.1 mg%) and 4.6 mg% (range = 1.4-9.2 mg%) in survivors (p c 0.05). The mean maximal bilirubin in survivors was 4.5 mg% (range 2.1-9.2 mg%), which was significantly (p 0.05) lower than in those patients who died of causes other than hepatic failure (mean = 13.8 mg%; range 5.8-22 mg%) or directly as a consequence of hepatic failure (mean 25.2 mg%, range = 16-30 mg%). Serum glutamic oxalacetic transaminase (SGOT) (normal = 7-26 IU/l). All patients except one showed an
with a febrile course. No patients had received isoniazid. Azathioprine and prednisone were stopped or markedly decreased with bilirubin elevation or suspected sepsis. In the survivors azathioprine was gradually restarted. In two patients (patient 15, Table 6; patient 19, Table 7; one with pseudomonas sepsis and the other with septic pancreatitis) cyclophosphamide was substituted for azathioprine shortly before death. Only one of the surviving patients was restarted on cyclophosphamide rather than azathioprine following her jaundice and this patient had chronic active hepatitis documented histologically at death. Laboratory values. Laboratory values did not provide important information regarding the differential diagnosis of jaundice. Serum creatinine. In 21 patients serum creatinine was
=
=
=
TABLE 6. Liver Failure Secondary to Sepsis CMV/HVH & VZ Serology Pt #
Age/Sex/ Kidney Source
15
29/M/LRD
WBC 1:4)
Bact. Cultures (Pathogen)
HVH
Liver Pathology
TTiter
Months Posttx
HB,Ag
(Early)
PreJD
28
-
+
ND
AtJD
>2?
+/
-/
Clin
PM
Clin
PM
Early
Late/PM
+
-
-
-
+
+
Bx: Cholestasis; portal
fibrosis PM: Centrilobular cholestasis PM: Fatty metamorphosis; cholestasis; no necrosis
kidney 42/F/CAD
16
13
-
-
+/
-
+
-
-
+
+
urine 49/M/CAD
17
3
-
-
+/+
+/+
-/ .
.
.
.
.
+
PM: Candidiasis; cholestasis
+
Outcome
(Biopsy or PM)
Death in 2 months of
sepsis Death of Staph. sepsis
secondary to bacterial valvular infection Death of candida +
bacterial
superimposed sepsis Total # = 3 JD
=
jaundice. Clin
ms = =
14.6
0/3
clinical. PM
=
1/3
postmortem. Bx
2/2 =
2/3
0/3
2/3
0/3
biopsy. CAD = cadaver donor. LRD
0/3 =
0/3
3/3
Death = 3/3
3/3
living related donor. ND
=
not done. rm = mean.
Vol. 188 * No. 6
787
ALLOTRANSPLANTATION
TABLE 7. Hepatitis of Undetermined Etiology CMV/HVH & Viral Cultures
VZ Serology
Months Posttx
HB,Ag
WBC 1:4)
Bact. Cultures (Pathogen)
HVH
Liver Pathology (Biopsy or PM)
AtJD
TTiter >22
Clin
PM
Clin
PM
Early
Late/PM
+/
+1+
-,'-
-
+
+
-
-
-
-
+/
+/
-/-
-
-
-
-
+
-
-
-/ -
-/ +/+
?*
-
+ liver ND ND
-
ND ND
-
-
PM: Massive hepatic necrosis Bx & PM: Centrilobular degeneration Bx: Cirrhosis and infiltrate ND
16
-
-
-
+/+
?*
-
ND
-
ND
-
-
Bx: Normal liver
di = 16.2
0/5
0/5
2/5
4/5
0/5?
0/5
2/2
1/5
0/2
0/5
1/5
PreJD
Outcome Death of liver failure
Death due to septic pancreatitis Alive. CAH Alive. Normal liver enzyme Death. Crypt. meningitis. CAH.
Tbilirubin Death = 3/5 CAH = 1/2 (surv.)
* No recent titers for comparison. JD = jaundice. Clin = clinical. PM = postmortem. Bx = biopsy. CAD = cadaver donor. LRD = living related donor. ND = not done. CAH = chronic active hepatitis. ib = mean.
elevation of SGOT. The mean maximal value in patients who expired was 585 1U/l (range = 20-3700 1U/l) versus a mean of 268.2 IU/l (range = 120-579 IU/l) in survivors. Alkaline phosphatase (normal = 60-220 lU/l). The initial values in the survivor group was a mean of 372 IU/I (175-864 IU/1) and in those who died 451 IU/I (175-740 IU/l). The maximal values in survivors was a mean of 584 IU/I (175-1220 IU/l) and in those who died the mean was 747 IU/I (range = 625-3402 IU/1). There were no consistent elevation patterns associated with the various etiologies. Serum lactic dehydrogenase (LDH) (normal = 130309 lU/l). The survivors had an initial mean of 333 IU/I (range = 90-553 IU/l) and a maximal mean of 689 IU/I (range = 590-1050 IU/l). In those patients who died, the initial mean was 670 IU/l (range = 590-1050 IU/I) and the maximal mean was 1653 IU/I (range = 5703007 IU/l). These differences are significant (p < 0.01). Again, no distinction could be made as to etiology. None of these patients were jaundiced on the basis of biliary calculi or biliary tract disease. Analysis for Primary Etiology Tables 3-7 summarize the bacterial, viral and pathological data we used in categorizing the patients along the lines of "most probable primary etiology" for their jaundice. Clinical and biochemical features are omitted from these tables because they seemed to be of no use in making the differential diagnosis of prognostic value. An exception to this statement is made for the time interval from transplantation to the onset of jaundice, which tended to be short (one to two months) in the "proven" cases with CMV hepatitis (Table 5). The decision to categorize these patients according to a single etiologic process based primarily on viral isolation and serological studies was difficult since most of these
patients (as in 80% of the general transplant population) had evidence of prior cytomegalovirus infection. Additionally a few had positive cytomegalic cultures. The decision was usually based on the recent appearance of a viral isolate or a recent seroconversion rather than the clinical pattern though clinical factors were taken into consideration. Viral hepatitis B (HBsAg positive hepatitis) (Table 3). Five patients were HBsAg positive at the time of jaundice; three of whom were also positive prior to transplantation. With the exception of patient 5 who became icteric and positive for HBsAg shortly after retransplantation, the mean interval from transplantation was nine months. Bacterial and cytomegalovirus infections did not appear to play important roles in the pathogenesis of the liver disease. Of the five patients, one died with the initial episode of jaundice, and two more patients died as a direct result of liver dysfunction, liver dysfunction was persistent in the other two, one of whom has died of other causes. Herpesvirus hominis (HVH) and Varicella Zoster (VZ) hepatitis (Table 4). Three patients appeared to have hepatitis due to herpesviruses other than CMV; two patients had HVH hepatitis and one had VZ hepatitis. Patients 7 and 8 (Table 4) showed strong CMV seroconversion at two months after illness and a contribution of CMV to the hepatitis cannot be ruled out. All three patients were young females (ages 19-21 years). Patients 6 and 7 developed herpes progenitalis. Patient 6 had an acute fulminant course with systemic disease terminating in liver failure death in less than one month. Viral cultures were positive for HVH from blood and urine and massive hepatic necrosis was accompanied by typical HVH inclusions. Patient 7 recovered after a febrile illness, mild jaundice (bilirubin 3.0 mg%) and had had positive cultures for HVH for two months prior to jaundice. She seroconverted to both
788
MOZES AND OTHERS
HVH and CMV during this illness but CMV was never cultured. Patient 8 developed jaundice during a febrile illness with VZ with a painful rash in a polydermatomal distribution. Seroconversion (1:512) to VZ resulted during this illness. She was treated with adenine arabinoside and temporary cessation of azathioprine and recovered without sequelae. An important prognostic factor among these patients may be the development of strong seroconversion seen in the two patients who ultimately recovered. Cytomegalovirus (CMV) hepatitis (Table 5a). Four patients presented with strong evidence of CMV isolation from liver tissue either antemortum or at autopsy. All had developed the viral syndrome in the first two months after transplantation. Three of the four had significant leukopenia. Serial antibody studies were available for three patients; two had complement-fixing antibodies to both CMV and HVH, all three had CF antibodies to CMV but only one patient seroconverted (1:64) at the time of illness. All four patients died. The causes of death and liver pathology are noted in Table Sa. Suspected cytomegalovirus (CMV) hepatitis (Table Sb). Two patients are also suspected of CMV hepatitis. The first, patient 13 (Table 5b) had a nearly fatal CMV infection at two months after transplantation, at which time he seroconverted to CMV (1:4096) and recovered. Almost two years later he presented with mild renal malfunction which was treated as rejection. This was followed by severe leukopenia, jaundice and a fulminant and fatal course of liver failure. Unfortunately, viral tests and an autopsy were not performed. The second patient was a child who developed a febrile illness with leukopenia, mild jaundice shortly after transplantation and recovered. Viral diagnostic data are not available, but CMV infection is very likely on the basis of the clinical presentation.37 This patient subsequently died with systemic varicella infection one year later. Jaundic e sec ondary to bac terial orfungal sepsis (Table 6). Three patients developed jaundice secondary to fatal bacterial or fungal systemic sepsis. The diagnosis became apparent in all three based on routine culture results. Two of these three patients had evidence of presence of CMV at time of illness but CMV could not be implicated as an etiology for their jaundice or death. Hepatitis of undetermined etiology (Table 7). This group of five patients did not present with a clearly defined etiology of jaundice. The patients tended to be in the older age group and the onset of jaundice was not early after transplantation. They presented with symptoms typical of hepatitis (fatigue, anorexia) but without fever. Only patient 18 presented with fever and she had pneumonitis at the time. They were free of
Ann. Surg. a December 1978
bacterial or fungal infection; the only sepsis being predeterminal in patient 19 who died of pancreatitis and peritonitis following a negative biliary tract exploration. The CMV viral serology was positive in four (80%) but there were no documented seroconversions or positive viral cultures during the illness or subsequently (except the virus isolated from the liver of patient 19). The liver biopsies performed were not diagnostic. Patient 22 had normal appearing liver. One patient died in fulminant liver failure. Half the survivors have evidence for chronic liver dysfunction on long-term follow-up. The liver disease in these five patients may be drug related or associated with an as yet undetermined viral agent. Discussion Although chemical evidence of liver dysfunction has been frequently noted (7-67%) among kidney transplant recipients, 1.4,7,8.14,18,24,30,32,34,45 we have not prospectively followed liver function studies in our patients and the true incidence of hepatic malfunction in the Minnesota series is unknown. The incidence of clinical jaundice in this retrospective study was 4%, within the range of 2-9% found by others." 4'8'32'34 Many factors can cause minimal or severe liver disease in transplant patients and neither the causes nor cures are readily apparent. Most of the patients (91%) had no history of prior liver disease. The two exceptions were patients with history of positive HBsAg (one associated with clinical hepatitis). Pretransplant HBs antigenemia is not thought to carry an increased risk of posttransplant liver failure.9'32'36 However considerable controversy remains regarding this point.4'23'3'33'42'43 The interval time between transplantation and development of jaundice varied widely; from less than one month to eight years. There is, however, a definite tendency for the jaundice due to CMV infection to occur earlier (M < 2.5 months) than jaundice associated with other etiologies. In this regard, of a group of 23 patients, the six (25%) who developed jaundice within two months of transplantation were still receiving large doses of immunosuppressive therapy. High dose azathioprine may be related to direct hepatotoxicity4l'47 or increased susceptibility to viral hepatitis.5 46 Two patients also succumbed to progressive liver failure after high dose steroid treatment for supposed "rejection" in the face of mild jaundice. Both had a viral component to their illness. Ninety per cent of patients in this series had good renal function at the onset of jaundice and in those patients who survived there was no deterioration of renal function, even in patients in whom azathioprine was stopped for prolonged periods. The maintenance of renal function in the absence of immunosuppressive
Vol. 188 - No. 6
agents has been observed previously,17'20 and might be of therapeutic importance especially in the management of infectious liver disease. The initial clinical syndrome was not diagnostic as to etiology with the exception of the following: 1) mucocutaneous manifestations of HVH and VZ preceded the evidence for liver involvement by two weeks or longer, and 2) prolonged, spiking fever (>101°F), less than 60 days after transplantation is strongly suggestive for CMV infection. Blood chemistries were not discriminative in terms of the differential diagnosis or
prognosis. 1'24
789
ALLOTRANSPLANTATION
Other diagnostic measures such as liver scans and cholangiography have not been helpful. Retrograde cannulations and exploratory laparotomy have all been negative. In none of these patients was obstructive biliary calculus disease encountered, in agreement with others' series 1,4,7,8,14,18,24,30,32.45 For this reason extensive diagnostic studies to rule out obstructive etiologies are not warranted. We have not demonstrated the usefulness of liver biopsy in our series; no changes were made in either diagnosis or treatment on the basis of histologic findings at biopsy. This probably reflects the fact that most were performed late in the clinical course. In contrast, other transplant groups have found biopsy useful, both in planning treatment (e.g., substitution of one immunosuppressive agent for another) or as a prognostic variable.1845 Using the parameters outlined in Tables 3-7 as well as "suggestive" clinical features we have established various etiologic diagnoses. However, in 30% of patients, even in retrospect no definite etiology can be established. Similar reservations must be made with respect to many papers on this subject.' 4.7'8"14'18'24,3032 We can say that clinical hepatitis due to hepatitis B is uncommon as compared to the number of carriers in the population but when clinical jaundice due to HBsAg appears it is usually unremitting and fatal.23'31'34.42.43 Nevertheless, our evidence does not support the idea that dialysis patients positive for HBsAg should categorically be denied transplant. This posttransplant incidence of CMV infection is between 75_90%. 2.3.5,11,16.19.38,39.46 The spectrum of liver dysfunction with CMV infection ranges from mild hepatocellular dysfunction to liver failure and death." 3,21,24,45 As in the case of HBSAg hepatitis, we do not know the incidence of hepatic involvement in all our patients with documented CMV infection because of the lack of a prospective study of hepatic function. Three causes of jaundice offer fewer diagnostic problems. 1) HVH is a rare cause of severe hepatitis appearing in newborn infants and young children with disseminated infection15,27 and occasionally in transplant recipients. 2022'29'40 Jaundice accompanies mucocutaneous vesicular eruptions and the diagnosis can be
established by detection of inclusion bodies from mucosal lesions or liver biopsy. 2) Varicella zo.ster hepatitis is even more rare but effective treatment for herpes zoster infection has now been established in the use of arabinoside A. Zoster immune plasma has been established as useful prophylaxis after herpes zoster exposure but its usefulness in treatment is doubtful." 3) Hepatic failure due to systemic bacterial and fungal sepsis has long been recognized although the mechanisms involved are poorly understood.'3 '8 44 It carries an ominous prognosis. 13.18.44 The cause for hepatitis in a substantial group of patients is not readily apparent, and in fact the illness is probably associated with multiple causes. Among the common etiologic factors suggested are unidentified viral agents10'14.45 and drug toxicity with azathioprine receiving prime consideration. Whereas early work by Starzl et al. showed that azathioprine in high doses (2-4 mg/kg/day) can cause hepatocellular necrosis in dogs,41 other workers34 suggest that there is no conclusive evidence that azathioprine is an important hepatotoxic agent in man. Since azathioprine can be stopped with relative safety7'18.4; it would appear that cessation of azathioprine with or without the substitution of cyclophosphamide should be recommended. Other drugs with known hepatotoxic effects are a-methyl dopa, isoniozide,25 acetaminophin,28 sulfisoxazole and chlorpromazine. Although we do not feel that the liver failure developing in our patients could be definitively attributed to these drugs, a cessation of these and other known hepatotoxic drugs is in order when dealing with these circumstances. Ten years ago Moore and Hume:0 discussed the causes of death following transplantation and pointed out that "'hepatitis was frequent." Hepatic malfunction appears to be the third leading cause of death following renal transplantation. It is apparent that a number of viruses which cause other syndromes in these transplant patients will, on occasion, be associated with hepatic malfunction, acute hepatitis and more seriously chronic active hepatitis. Very little progress in this area has been made because of a lack of clinical virological correlation for the subclinical illness as well as the severe jaundice. This paper primarily points out the numerous etiologies that can be involved, the difficulty of distinguishing one from the other on clinical ground and the need for precise clinical-virological prospective studies in this susceptible population. References I. Aldrete, J. S., Sterling, W. A., Hathaway, B. M., et al.: Gastrointestinal and Hepatic Complications Affecting Patients with Renal Transplants. Am. J. Surg., 129:115, 1975. 2. Andersen, H. K. and Spencer, E. S.: Cytomegalovirus Infection Among Renal Allograft Recipients. Acta Med. Scand., 186:7, 1969. 3. Armstrong, D., Balakrishnan, S. L., Steger, L., et al.: Cyto-
790
MOZES AND OTHERS
megalovirus Infections with Viremia Following Renal Transplantation. Arch. Int. Med., 127:111, 1971(a). 4. Aronoff, A., Gault, M. H., Huang, S. N., et al.: Hepatitis with Australia Antigenemia Following Renal Transplantation. Can. Med. Assoc. J., 108:43, 1973. 5. Back, J.-F. and Dardenne, M.: Serum Immunosuppressive Activity of Azathioprine in Normal Subjects and Patients with Liver Diseases. Proc. R. Soc. Med., 65:260, 1972. 6. Balfour, H. H., Jr., Groth, K. E., McCullough, J., et al.: Prevention or Modification of Varicella Using Zoster Immune Plasma. Am. J. Dis. Child., 131:693, 1977. 7. Berne, T. V., Chatterjee, S. N., Craig, J. R. and Payne, J. E.: Hepatic Dysfunction in Recipients of Renal Allografts. Surg. Gynecol. Obstet., 141:171, 1975. 8. Briggs, W. A., Lazarus, M. J., Birtch, A. G., et al.: Hepatitis Affecting Hemodialysis and Transplant Patients-its Consideration and Consequences. Arch. Int. Med., 132:21, 1973. 9. Chatterjee, S. N., Payne, J. E., Bischel, M. D., et al.: Successful Renal Transplantation in Patients Positive for Hepatitis B Antigen. N. Eng. J. Med., 291:62, 1974. 10. Conrad, M. E. and Knodell, R. G.: Viral Hepatitis (Commentary). J.A.M.A., 233:1277, 1975. 11. Craighead, J. E., Hanshaw, J. B. and Carpenter, C. B.: Cytomegalovirus Infection after Renal Allotransplantation. J.A.M.A., 201:725, 1967. 12. Eddleston, A. L. and Williams, R.: Inadequate Antibody Response to HBAg or Suppressor T-cell Defect in Development of Active Chronic Hepatitis. Lancet, 2:1543, 1974. 13. Fahrlander, H., Huber, F. and Gloor, F.: Intrahepatic Retention of Bile in Severe Bacterial Infections. Gastroenterology, 47: 590, 1964. 14. Freiberger, Z., Armras, G., Koff, R. S. and Bonney, W. W.: Chronic Active Hepatitis Without Hepatitis B Antigenemia in Renal Transplant Recipients. Gastroenterology, 66:1187, 1974. 15. Hathaway, W. E., Mull, M. M. and Pechet, G. S.: Disseminated Intravascular Coagulation in the Newborn. Pediatrics, 43:233, 1969. 16. Hill, R. B., Jr., Rowland, D. T., Jr. and Rifkind, D.: Infectious Pulmonary Disease in Patients Receiving Immunosuppressive Therapy for Organ Transplantation. N. Engl. J. Med., 271: 1021, 1964. 17. Hume, D. M., Lee, H. M., Williams, G. M., et al.: Discontinuation of Azathioprine with Maintenance of Renal Function. Ann. Surg., 164:352, 1966. 18. Ireland, P., Rashid, A., von Lichtenbery, F., et al.: Liver Disease in Kidney Transplant Patients Receiving Azathioprine. Arch. Intern. Med., 132:29, 1973. 19. Javitt, B. N.: Chronic Active Hepatitis. Am. J. Med., 55:733, 1973. 20. Klemola, E., Stenstrom, R. and von Essen, R.: Pneumonia as a Clinical Manifestation of CMV Infection in Previously Healthy Adults. Scand. J. Infect. Dis., 4:7, 1972. 21. Leinikki, P., Heinonen, K. and Pettay, O.: Incidence of Cytomegalovirus Infections in Early Childhood. Scand. J. Infect. Dis., 4:1, 1972. 22. Lee, J. C. and Fortuny, E. I.: Adult Herpes Simplex Hepatitis. Hum. Pathol. 3:277, 1972. 23.' Levine, A. R. and Ranek, L.: Asymptomatic Chronic Hepatitis -Correlations Between Isolated Serum Transaminase Abnormality and Liver Biopsy. Gastroenterology, 58:371, 1970. 24. Luby, J. P., Burnett, W., Hull, A. R., et al.: Relationship Between Cytomegalovirus and Hepatic Function Abnormalities in the Period after Renal Transplant. J. Int. Dis., 129:511, 1974. 25. Maddrey, W. C. and Boitnott, J. K.: Hepatitis Induced by Isoniazid and Methyldopa. Hospital Practice, 10: 119, 1975. 26. Millard, P. R., Herbertson, B. M., Evans, D. B. and Colne,
27. 28. 29. 30. 31.
32. 33. 34. 35. 36. 37.
38. 39. 40.
41.
42.
43. 44. 45. 46. 47.
Ann. Surg. * December 1978
R. Y.: Azathioprine Hepatotoxicity in Renal Transplantation. Transplantation, 16:527, 1973. Miller, D. R., Hanshaw, J. B., O'Leary, D. S. and Huilicka, J. V.: Fatal Disseminated Herpes Simplex Virus Infection and Hemorrhage in the Neonate. J. Pediat., 76:409, 1970. Mitchell, J. R.: Drugs and the Liver. Viewpoints on Dig. Dis., 6(No. 5), 1974. Montgomerie, J. Z., Becroft, D. M. O., Crokson, M. C., et al.: Herpes-Simplex-Virus Infection after Renal Transplantation. Lancet, 11:867, 1969. Moore, T. C. and Hume, D. H.: The Period and Nature of Hazard in Clinical Renal Transplantation. Ann. Surg., 1970: 1, 1969. Nielsen, J. O., Dietrichson, O., Elling, P. and Christofferson, P.: Incidence and Meaning of Persistence of Australia Antigen in Patients with Acute Viral Hepatitis-Development of Chronic Hepatitis. N. Engl. J. Med., 285:1157, 1971. Nielsen, V., Clausen, E. and Ranek, L.: Liver Impairment During Hemodialysis and after Renal Transplantation. Acta Med. Scand., 197:229, 1975. Pirson, Y., Alexandre, G. P. and Ypersele, C.: Long-term effect of hbs Antigenemia on Patient Survival after Renal Transplantation. N. Engl. J. Med., 296:194, 1977. Pirson, Y., Van Ypersele de Strihou, C., Noel, I. I., et al.: Liver Disease in Transplanted Patients. Proc. Eur. Dial. Transplant Assoc., 10(0):434, 1973. Robinson, M. G. and Kaufman, S.: Disseminated Herpes Simplex, a Cause of Consumptive Coagulopathy. Soc. Ped. Res. Abstr. 103, 1969. Shons, A. R., Simmons, R. L., Kjellstrand, C. M., et al.: Renal Transplantation in Australia Antigenemia. Am. J. Surg., 128(5):699, 1974. Simmons, R. L., Kjellstrand, C. M. and Najarian, J. S.: Kidney transplantation: Technique, Complications and Results. In Najarian, J. S. and Simmons, R. L., eds., Transplantation. Philadelphia, Lea & Febiger, 1972, p. 445. Simmons, R. L., Lopez, C., Balfour, H., et al.: Cytomegalovirus: Clinical Virological Correlations in Renal Transplant Recipients. Ann. Surg. 180:623, 1974. Spencer, E. S.: Cytomegalovirus Antibody in Uremic Patients Prior to Renal Transplantation. Scand. J. Infect. Dis., 6:1, 1974. Spencer, E. S. and Anderson, H. K.: Clinically evident, nonterminal infections with herpes viruses and the wart virus in immunosuppressed renal allograft recipients. Br. Med. J. 3:251, 1970. Starzl, T. E., Marchioro, T. L., Porter, K. A., et al.: Factors Determining Short and Long-term Survival after Orthotopic Liver Homotransplantation. Surgery, 58:131, 1965. Torisu, M., Yokoyama, T., Amenisya, H., et al.: Immunosuppression, Liver Injury, Hepatitis in Renal, Hepatic and Cardiac Homograft Recipients: with Particular Reference to Australia Antigen. Ann. Surg., 174:620, 1971. Vittal, B. S., Thomas, W., Jr. and Clowdus, B. F.: Acute viral hepatitis-Course and Incidence of Progression to Chronic Hepatitis. Am. J. Med., 55:757, 1973. Vermillion, S. E., Gregg, J. A., Baggenstoss, A. H. and Bartholomew, L. G.: Jaundice Associated with Bacteremia. Arch. Int. Med., 124:611, 1969. Ware, A. J., Luby, J. P., Eigenbrodt, E. H., et al.: Spectrum of Liver Disease in Renal Transplant Recipients. Gastroenterology, 68:755, 1975. Whelan, G. and Sherlock, S.: Immunosuppressive Activity in Patients with Active Chronic Hepatitis and Primary Biliary Cirrhosis Treated with Azathioprine. Gut, 13:907, 1972. Zarday, A., Veith, F.-J., Gliedman, M. L. and Soberman, R.: Irreversible Liver Damage after Azathioprine. J.A.M.A., 222: 690, 1972.
Of 567 patients receiving renal transplantation at the University of Minnesota between October 1%7 and October 1975, 22 developed clinical jaundice. Of these 22, nine died with their initial episode of hepatitis, six died within three months of causes associated with liver malfunction, four developed evidence of chronic hepatic failure and only three totally recovered from their illness. Five had clear evidence of Australia antigen positive hepatitis B, four of cytomegalovirus hepatitis, two of herpes hominis hepatitis, one of varicella zoster hepatitis and three of hepatic failure associated with systemic bacterial and/or fungal sepsis. Two of the 22 patients were thought likely to have cytomegalovirus hepatitis though definite proof was absent and in five patients a clear-cut etiology could not be made. In many of these patients the diagnosis was confounded by the previous presence of HB,Ag antigen and the frequent occurrence of a previous or concurrent infection with cytomegalovirus. The role of various drugs including azathioprine, sulfisoxazole, chlorpromazine, acetominophen, etc., could not be established but major roles for these agents in the face of the many viral and bacterial infections present in these patients is doubted. No clear-cut therapy could be established although it appears safe to discontinue azathioprine for longer or shorter periods of time with or without substitution of cyclophosphamide without serious deterioration of renal function. The problem of hepatic failure in transplant patients is still unsolved and will require a prospective study of etiologic agents and sub-clinical hepatic dysfunction in order to establish even the first principles of clinical-pathological correlation.
EPATIC DYSFUNCTION iS seen frequently after re1"4'7'8,14,18,24,30,32'45 The renal transplantation. ported incidence depends on the criteria used to make the diagnosis and varies from 7% (four-fold elevations of transaminases or serum bilirubin greater than 2 mg%))4'718.30 to 67% (two-fold abnormal dye retention).4 Whereas most of these enzyme abnormalities are of indeterminate clinical significance,4 a small per cent of patients progress to frank liver disease and
death. Identification and early institution of therapy in these high risk patients may improve their poor prognosis. The etiologies of liver dysfunction have been attributed to a variety of viral and/or pharmacologic agents Reprint requests: Martin F. Mozes, M.D., Department of Surgery, University of Illinois at the Medical Center, Chicago, Illinois 60680. Submitted for publication: November 12, 1977.
From the Departments of Surgery and Laboratory Medicine/Pathology, University of Minnesota, Minneapolis, Minnesota
for which the evidence is circumstantial. Questions still exist regarding the proper treatment and whether or not immunosuppressive agents4'7'8'34'45 should be changed. This study was designed to review, in a large kidney recipient group from a single medical center, those patients who developed the more severe form of hepatic dysfunction, i.e. those with jaundice. In this group of 22 patients we have attempted to define the mode of clinical presentation, a useful diagnostic approach, etiologic classification and prognostic guidelines. Materials and Methods From October 1967 to October 1975, 567 patients received 661 renal allografts at the University of Minnesota; 271 were from cadaveric donors and 390 from living related donors. The methods of patient selection, techniques of transplantation and methods of immunosuppression have been described elsewhere.37 Twenty-two patients have been identified who developed clinically apparent jaundice at some time during their posttransplant course. Only patients with a serum bilirubin of 2.0 mg% or higher were selected for this study (normal range = 0.1-1.6 mg%). (Patients who demonstrated liver enzyme abnormalities without bilirubin elevation were not included.) All 22 patients were admitted to the hospital at the time of their illness. This patient group was analyzed for the clinical, biochemical, pharmacological, microbiological and histopathological aspects of their illness. All survivors have been followed (27 months to seven years) with regard to longterm survival, kidney graft function and liver function status. Detailed autopsies, including viral and bacterial cultures, were performed on 15 of the 17 patients who died. Particular attention was paid to chemical abnormalities, i.e., blood urea nitrogen (BUN), creatinine, bilirubin, glutamicoxaloacetic transaminase
0003-4932/78/1200/0783 $00.90 C J. B. Lippincott Company
783
784
Ann. Surg. * December 1978
MOZES AND OTHERS TABLE 1. Characteristics oflcteric Transplant Patients
Transplant Number Period (Inclusive)
Total Number of Transplants
Total Number of Patients
Number of Icteric Patients
M:F
Oct. 1967-Oct. 1975
661
567
22 (4%)
11:11
Mean Age* (Range)
LRD:CAD
1st
2nd
34.3
11:11
19
3
(20-53) *
One child age 31/2 years not included. M
=
male. F
=
female. LRD
(SGOT), alkaline phosphatase, lactic-dehydrogenase (LDH) and serum protein electrophoresis. In order to gain prognostic information, liver function studies were noted at the onset of liver dysfunction, as well as the maximal level attained. Microbiological studies included standard aerobic and anaerobic bacterial cultures and fungal cultures. Serology for hepatitis B (HB,Ag) antigen was performed by both counter electrophoresis (CEP) and radioimmunoassay (RIA). Viral serology for complement fixing antibody (CF) against cytomegalovirus (CMV), herpesvirus hominis (HVH) and varicella zoster (VZ) was obtained. Viral cultures for these viruses utilized methods previously described.:8 An antibody titer 1:4 was considered positive and a two-fold rise of titer was considered evidence of recent viral infection. Patients were additionally grouped according to the most likely primary etiology in each case. Results
Clinical Profile and Prognostic Significance of Clinical Facctors
Age and donor source (Table I). Among the 22 patients with clinically apparent jaundice, there were ten adult males and 11 females with a mean age of 36.0 and 32.9 years respectively. There was one male child 3.5-years-old. Nineteen patients had received one kidney transplant and three patients received two transplants. Eleven patients received kidney grafts from living related donors and 11 from cadaveric donors (Table 1) (there is a greater than 4:3 ratio of recipients
=
living related donor. CAD
=
cadaver donor.
of related transplants to recipients of cadaver transplants in our entire series). Time interval, transfusion history, and renal function. In 18 of 22 patients, the duration of dialysis before transplantation was less than six months but all patients received blood transfusions either while on dialysis or in the course of their operations (bilateral nephrectomy and splenectomy and/or transplantation). The time interval between transplantation and the onset of icterus was less than six months in ten of the 22 patients (in six of ten it was less than six weeks, Tables 2-7). In 12 patients, the interval varied from 8-39 months and in one patient it was over eight years. Patients with CMV hepatitis had a shorter interval from transplant to jaundice (see below). With the exception of one patient who developed jaundice shortly after removal of a second rejected graft, almost all of 22 patients became icteric with good renal function (serum creatinine 22
+/
-/
Clin
PM
Clin
PM
-
+
Early
Late/PM
-
-
Bx: cirrhosis PM: massive hepatic necrosis
-
-
ND ND
-
+
2 3
35/F/LRD 41/M/CAD
12 12
+ +
-
+/
+/-/
-/ -/
-
4
21/M/CAD#2
8
+
-
+/-
+/-
+/-
-
ND
-
ND
-
-
PM: coarse nodular cirrhosis & CAH
5
21/F/CAD#2
1:4)
HB,Ag
(Early)
21/F/LRD
7 yrs
-
+
-/
20/F/LDR 19/F/LRD
28 2
-
-
*-+
+
+/+ -/-
++
-
-/-
+
Total # = 3
-
0/3
2/3
1/3
1/3
0/3
Kidney Source
6 7
HVH
Bact. Cultures (Pathogen)
Liver Pathology
TTiter
Months Posttx
Pt #
8
WBC 22
AtJD
PreJD .
Clin .
.
* Significant rise in CMV antibody titer (1:512) two months following illness. JD related donor. CAH = chronic active hepatitis. ND = not done.
.
0/3
=
PM
0/3
Clin
PM
/+ /+ blood liver /+ /1/3
jaundice. Clin
1/3
=
Early
Late/PM
-
-
-
-
-
+
0/3
1/3
clinical. PM
=
Outcome
(Biopsy or PM) PM: submassive hepatic necrosis; H. Hominis ND ND
postmortem. Bx
Death in liver failure; diffuse bleeding Alive and well Alive and well Dead = 1/3 CAH = 0/2
=
biopsy. CAD
=
cadaver donor. LRD
=
living
Ann. Surg. * December 1978
MOZES AND OTHERS
786
TABLE 5a. Cytomegalovirus (CMV) Hepatitis CMV/HVH & VZ Serology Pt #
Age/Sex/ Kidney Source
Months Posttx
HB,Ag
WBC 1:4)
PreJD
AtJD
tTiter >22
Clin
+1-
+1+
-1-
+
Bact. Cultures (Pathogen)
HVH
PM
Clin
PM
Early
Late/PM
+
-
-
+*
-
-
-
-
+
PM: Plasmacell and lymph infiltrate; CMV inclusions Bx & PM: Cholestasis; focal necrosis; CMV inclusions PM: Bile stasis; fatty changes Bx & PM: Massive hepatic necrosis
liver 10
25/M/LRD
I
+
+
-I
-I
-I
11
30/F/LRD
I
-
+
+/+
+/+
+/
-
+
-
-
-
+
12
25/M/LRD
6
-
+
+/
-/
-/
+
+
-
-
-
+
mn = 2.5
1/4
3/4
3/4
2/4
1/4
3/4
4/4
0/4
0/4
1/4
3/4
Total # = 4
+ + liver liver
Liver Pathology (Biopsy or PM)
Outcome Death from bleeding secondary to liver biopsy Death with CMV pneumonia and respiratory failure Death of CMV; respiratory failure Death. Acute hemorrhagic pancreatitis and hepatic failure Death = 4/4
TABLE 5b. Probable Cytomegalovirus (CMV) Hepatitis 23 I
53/M/CAD
13 14
3.5/M/LRD
+ +
-
-
+/
+/+
?*
ND
ND
ND
* CMV antibody titer 1:256, but no recent titer available to confirm donor. m-n = mean. ND = not done.
ND ND
ND
rise. JD = jaundice. Clin
ND ND
ND =
-
+
-
-
Death of liver failure Death. Varicella
ND ND
clinical. PM = postmortem. Bx = biopsy. CAD
=
cadaver donor. LRD
=
living related
l1.5 mg% (Table 2). Renal function remained essentially without change throughout the illness and in all long term survivors. Serum bilirubin. On admission, serum bilirubin ranged from 1.4 to 11.1 mg%. The mean admission bilirubin level was 5.6 mg% in patients who subsequently died (range = 2.5-11.1 mg%) and 4.6 mg% (range = 1.4-9.2 mg%) in survivors (p c 0.05). The mean maximal bilirubin in survivors was 4.5 mg% (range 2.1-9.2 mg%), which was significantly (p 0.05) lower than in those patients who died of causes other than hepatic failure (mean = 13.8 mg%; range 5.8-22 mg%) or directly as a consequence of hepatic failure (mean 25.2 mg%, range = 16-30 mg%). Serum glutamic oxalacetic transaminase (SGOT) (normal = 7-26 IU/l). All patients except one showed an
with a febrile course. No patients had received isoniazid. Azathioprine and prednisone were stopped or markedly decreased with bilirubin elevation or suspected sepsis. In the survivors azathioprine was gradually restarted. In two patients (patient 15, Table 6; patient 19, Table 7; one with pseudomonas sepsis and the other with septic pancreatitis) cyclophosphamide was substituted for azathioprine shortly before death. Only one of the surviving patients was restarted on cyclophosphamide rather than azathioprine following her jaundice and this patient had chronic active hepatitis documented histologically at death. Laboratory values. Laboratory values did not provide important information regarding the differential diagnosis of jaundice. Serum creatinine. In 21 patients serum creatinine was
=
=
=
TABLE 6. Liver Failure Secondary to Sepsis CMV/HVH & VZ Serology Pt #
Age/Sex/ Kidney Source
15
29/M/LRD
WBC 1:4)
Bact. Cultures (Pathogen)
HVH
Liver Pathology
TTiter
Months Posttx
HB,Ag
(Early)
PreJD
28
-
+
ND
AtJD
>2?
+/
-/
Clin
PM
Clin
PM
Early
Late/PM
+
-
-
-
+
+
Bx: Cholestasis; portal
fibrosis PM: Centrilobular cholestasis PM: Fatty metamorphosis; cholestasis; no necrosis
kidney 42/F/CAD
16
13
-
-
+/
-
+
-
-
+
+
urine 49/M/CAD
17
3
-
-
+/+
+/+
-/ .
.
.
.
.
+
PM: Candidiasis; cholestasis
+
Outcome
(Biopsy or PM)
Death in 2 months of
sepsis Death of Staph. sepsis
secondary to bacterial valvular infection Death of candida +
bacterial
superimposed sepsis Total # = 3 JD
=
jaundice. Clin
ms = =
14.6
0/3
clinical. PM
=
1/3
postmortem. Bx
2/2 =
2/3
0/3
2/3
0/3
biopsy. CAD = cadaver donor. LRD
0/3 =
0/3
3/3
Death = 3/3
3/3
living related donor. ND
=
not done. rm = mean.
Vol. 188 * No. 6
787
ALLOTRANSPLANTATION
TABLE 7. Hepatitis of Undetermined Etiology CMV/HVH & Viral Cultures
VZ Serology
Months Posttx
HB,Ag
WBC 1:4)
Bact. Cultures (Pathogen)
HVH
Liver Pathology (Biopsy or PM)
AtJD
TTiter >22
Clin
PM
Clin
PM
Early
Late/PM
+/
+1+
-,'-
-
+
+
-
-
-
-
+/
+/
-/-
-
-
-
-
+
-
-
-/ -
-/ +/+
?*
-
+ liver ND ND
-
ND ND
-
-
PM: Massive hepatic necrosis Bx & PM: Centrilobular degeneration Bx: Cirrhosis and infiltrate ND
16
-
-
-
+/+
?*
-
ND
-
ND
-
-
Bx: Normal liver
di = 16.2
0/5
0/5
2/5
4/5
0/5?
0/5
2/2
1/5
0/2
0/5
1/5
PreJD
Outcome Death of liver failure
Death due to septic pancreatitis Alive. CAH Alive. Normal liver enzyme Death. Crypt. meningitis. CAH.
Tbilirubin Death = 3/5 CAH = 1/2 (surv.)
* No recent titers for comparison. JD = jaundice. Clin = clinical. PM = postmortem. Bx = biopsy. CAD = cadaver donor. LRD = living related donor. ND = not done. CAH = chronic active hepatitis. ib = mean.
elevation of SGOT. The mean maximal value in patients who expired was 585 1U/l (range = 20-3700 1U/l) versus a mean of 268.2 IU/l (range = 120-579 IU/l) in survivors. Alkaline phosphatase (normal = 60-220 lU/l). The initial values in the survivor group was a mean of 372 IU/I (175-864 IU/1) and in those who died 451 IU/I (175-740 IU/l). The maximal values in survivors was a mean of 584 IU/I (175-1220 IU/l) and in those who died the mean was 747 IU/I (range = 625-3402 IU/1). There were no consistent elevation patterns associated with the various etiologies. Serum lactic dehydrogenase (LDH) (normal = 130309 lU/l). The survivors had an initial mean of 333 IU/I (range = 90-553 IU/l) and a maximal mean of 689 IU/I (range = 590-1050 IU/l). In those patients who died, the initial mean was 670 IU/l (range = 590-1050 IU/I) and the maximal mean was 1653 IU/I (range = 5703007 IU/l). These differences are significant (p < 0.01). Again, no distinction could be made as to etiology. None of these patients were jaundiced on the basis of biliary calculi or biliary tract disease. Analysis for Primary Etiology Tables 3-7 summarize the bacterial, viral and pathological data we used in categorizing the patients along the lines of "most probable primary etiology" for their jaundice. Clinical and biochemical features are omitted from these tables because they seemed to be of no use in making the differential diagnosis of prognostic value. An exception to this statement is made for the time interval from transplantation to the onset of jaundice, which tended to be short (one to two months) in the "proven" cases with CMV hepatitis (Table 5). The decision to categorize these patients according to a single etiologic process based primarily on viral isolation and serological studies was difficult since most of these
patients (as in 80% of the general transplant population) had evidence of prior cytomegalovirus infection. Additionally a few had positive cytomegalic cultures. The decision was usually based on the recent appearance of a viral isolate or a recent seroconversion rather than the clinical pattern though clinical factors were taken into consideration. Viral hepatitis B (HBsAg positive hepatitis) (Table 3). Five patients were HBsAg positive at the time of jaundice; three of whom were also positive prior to transplantation. With the exception of patient 5 who became icteric and positive for HBsAg shortly after retransplantation, the mean interval from transplantation was nine months. Bacterial and cytomegalovirus infections did not appear to play important roles in the pathogenesis of the liver disease. Of the five patients, one died with the initial episode of jaundice, and two more patients died as a direct result of liver dysfunction, liver dysfunction was persistent in the other two, one of whom has died of other causes. Herpesvirus hominis (HVH) and Varicella Zoster (VZ) hepatitis (Table 4). Three patients appeared to have hepatitis due to herpesviruses other than CMV; two patients had HVH hepatitis and one had VZ hepatitis. Patients 7 and 8 (Table 4) showed strong CMV seroconversion at two months after illness and a contribution of CMV to the hepatitis cannot be ruled out. All three patients were young females (ages 19-21 years). Patients 6 and 7 developed herpes progenitalis. Patient 6 had an acute fulminant course with systemic disease terminating in liver failure death in less than one month. Viral cultures were positive for HVH from blood and urine and massive hepatic necrosis was accompanied by typical HVH inclusions. Patient 7 recovered after a febrile illness, mild jaundice (bilirubin 3.0 mg%) and had had positive cultures for HVH for two months prior to jaundice. She seroconverted to both
788
MOZES AND OTHERS
HVH and CMV during this illness but CMV was never cultured. Patient 8 developed jaundice during a febrile illness with VZ with a painful rash in a polydermatomal distribution. Seroconversion (1:512) to VZ resulted during this illness. She was treated with adenine arabinoside and temporary cessation of azathioprine and recovered without sequelae. An important prognostic factor among these patients may be the development of strong seroconversion seen in the two patients who ultimately recovered. Cytomegalovirus (CMV) hepatitis (Table 5a). Four patients presented with strong evidence of CMV isolation from liver tissue either antemortum or at autopsy. All had developed the viral syndrome in the first two months after transplantation. Three of the four had significant leukopenia. Serial antibody studies were available for three patients; two had complement-fixing antibodies to both CMV and HVH, all three had CF antibodies to CMV but only one patient seroconverted (1:64) at the time of illness. All four patients died. The causes of death and liver pathology are noted in Table Sa. Suspected cytomegalovirus (CMV) hepatitis (Table Sb). Two patients are also suspected of CMV hepatitis. The first, patient 13 (Table 5b) had a nearly fatal CMV infection at two months after transplantation, at which time he seroconverted to CMV (1:4096) and recovered. Almost two years later he presented with mild renal malfunction which was treated as rejection. This was followed by severe leukopenia, jaundice and a fulminant and fatal course of liver failure. Unfortunately, viral tests and an autopsy were not performed. The second patient was a child who developed a febrile illness with leukopenia, mild jaundice shortly after transplantation and recovered. Viral diagnostic data are not available, but CMV infection is very likely on the basis of the clinical presentation.37 This patient subsequently died with systemic varicella infection one year later. Jaundic e sec ondary to bac terial orfungal sepsis (Table 6). Three patients developed jaundice secondary to fatal bacterial or fungal systemic sepsis. The diagnosis became apparent in all three based on routine culture results. Two of these three patients had evidence of presence of CMV at time of illness but CMV could not be implicated as an etiology for their jaundice or death. Hepatitis of undetermined etiology (Table 7). This group of five patients did not present with a clearly defined etiology of jaundice. The patients tended to be in the older age group and the onset of jaundice was not early after transplantation. They presented with symptoms typical of hepatitis (fatigue, anorexia) but without fever. Only patient 18 presented with fever and she had pneumonitis at the time. They were free of
Ann. Surg. a December 1978
bacterial or fungal infection; the only sepsis being predeterminal in patient 19 who died of pancreatitis and peritonitis following a negative biliary tract exploration. The CMV viral serology was positive in four (80%) but there were no documented seroconversions or positive viral cultures during the illness or subsequently (except the virus isolated from the liver of patient 19). The liver biopsies performed were not diagnostic. Patient 22 had normal appearing liver. One patient died in fulminant liver failure. Half the survivors have evidence for chronic liver dysfunction on long-term follow-up. The liver disease in these five patients may be drug related or associated with an as yet undetermined viral agent. Discussion Although chemical evidence of liver dysfunction has been frequently noted (7-67%) among kidney transplant recipients, 1.4,7,8.14,18,24,30,32,34,45 we have not prospectively followed liver function studies in our patients and the true incidence of hepatic malfunction in the Minnesota series is unknown. The incidence of clinical jaundice in this retrospective study was 4%, within the range of 2-9% found by others." 4'8'32'34 Many factors can cause minimal or severe liver disease in transplant patients and neither the causes nor cures are readily apparent. Most of the patients (91%) had no history of prior liver disease. The two exceptions were patients with history of positive HBsAg (one associated with clinical hepatitis). Pretransplant HBs antigenemia is not thought to carry an increased risk of posttransplant liver failure.9'32'36 However considerable controversy remains regarding this point.4'23'3'33'42'43 The interval time between transplantation and development of jaundice varied widely; from less than one month to eight years. There is, however, a definite tendency for the jaundice due to CMV infection to occur earlier (M < 2.5 months) than jaundice associated with other etiologies. In this regard, of a group of 23 patients, the six (25%) who developed jaundice within two months of transplantation were still receiving large doses of immunosuppressive therapy. High dose azathioprine may be related to direct hepatotoxicity4l'47 or increased susceptibility to viral hepatitis.5 46 Two patients also succumbed to progressive liver failure after high dose steroid treatment for supposed "rejection" in the face of mild jaundice. Both had a viral component to their illness. Ninety per cent of patients in this series had good renal function at the onset of jaundice and in those patients who survived there was no deterioration of renal function, even in patients in whom azathioprine was stopped for prolonged periods. The maintenance of renal function in the absence of immunosuppressive
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agents has been observed previously,17'20 and might be of therapeutic importance especially in the management of infectious liver disease. The initial clinical syndrome was not diagnostic as to etiology with the exception of the following: 1) mucocutaneous manifestations of HVH and VZ preceded the evidence for liver involvement by two weeks or longer, and 2) prolonged, spiking fever (>101°F), less than 60 days after transplantation is strongly suggestive for CMV infection. Blood chemistries were not discriminative in terms of the differential diagnosis or
prognosis. 1'24
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Other diagnostic measures such as liver scans and cholangiography have not been helpful. Retrograde cannulations and exploratory laparotomy have all been negative. In none of these patients was obstructive biliary calculus disease encountered, in agreement with others' series 1,4,7,8,14,18,24,30,32.45 For this reason extensive diagnostic studies to rule out obstructive etiologies are not warranted. We have not demonstrated the usefulness of liver biopsy in our series; no changes were made in either diagnosis or treatment on the basis of histologic findings at biopsy. This probably reflects the fact that most were performed late in the clinical course. In contrast, other transplant groups have found biopsy useful, both in planning treatment (e.g., substitution of one immunosuppressive agent for another) or as a prognostic variable.1845 Using the parameters outlined in Tables 3-7 as well as "suggestive" clinical features we have established various etiologic diagnoses. However, in 30% of patients, even in retrospect no definite etiology can be established. Similar reservations must be made with respect to many papers on this subject.' 4.7'8"14'18'24,3032 We can say that clinical hepatitis due to hepatitis B is uncommon as compared to the number of carriers in the population but when clinical jaundice due to HBsAg appears it is usually unremitting and fatal.23'31'34.42.43 Nevertheless, our evidence does not support the idea that dialysis patients positive for HBsAg should categorically be denied transplant. This posttransplant incidence of CMV infection is between 75_90%. 2.3.5,11,16.19.38,39.46 The spectrum of liver dysfunction with CMV infection ranges from mild hepatocellular dysfunction to liver failure and death." 3,21,24,45 As in the case of HBSAg hepatitis, we do not know the incidence of hepatic involvement in all our patients with documented CMV infection because of the lack of a prospective study of hepatic function. Three causes of jaundice offer fewer diagnostic problems. 1) HVH is a rare cause of severe hepatitis appearing in newborn infants and young children with disseminated infection15,27 and occasionally in transplant recipients. 2022'29'40 Jaundice accompanies mucocutaneous vesicular eruptions and the diagnosis can be
established by detection of inclusion bodies from mucosal lesions or liver biopsy. 2) Varicella zo.ster hepatitis is even more rare but effective treatment for herpes zoster infection has now been established in the use of arabinoside A. Zoster immune plasma has been established as useful prophylaxis after herpes zoster exposure but its usefulness in treatment is doubtful." 3) Hepatic failure due to systemic bacterial and fungal sepsis has long been recognized although the mechanisms involved are poorly understood.'3 '8 44 It carries an ominous prognosis. 13.18.44 The cause for hepatitis in a substantial group of patients is not readily apparent, and in fact the illness is probably associated with multiple causes. Among the common etiologic factors suggested are unidentified viral agents10'14.45 and drug toxicity with azathioprine receiving prime consideration. Whereas early work by Starzl et al. showed that azathioprine in high doses (2-4 mg/kg/day) can cause hepatocellular necrosis in dogs,41 other workers34 suggest that there is no conclusive evidence that azathioprine is an important hepatotoxic agent in man. Since azathioprine can be stopped with relative safety7'18.4; it would appear that cessation of azathioprine with or without the substitution of cyclophosphamide should be recommended. Other drugs with known hepatotoxic effects are a-methyl dopa, isoniozide,25 acetaminophin,28 sulfisoxazole and chlorpromazine. Although we do not feel that the liver failure developing in our patients could be definitively attributed to these drugs, a cessation of these and other known hepatotoxic drugs is in order when dealing with these circumstances. Ten years ago Moore and Hume:0 discussed the causes of death following transplantation and pointed out that "'hepatitis was frequent." Hepatic malfunction appears to be the third leading cause of death following renal transplantation. It is apparent that a number of viruses which cause other syndromes in these transplant patients will, on occasion, be associated with hepatic malfunction, acute hepatitis and more seriously chronic active hepatitis. Very little progress in this area has been made because of a lack of clinical virological correlation for the subclinical illness as well as the severe jaundice. This paper primarily points out the numerous etiologies that can be involved, the difficulty of distinguishing one from the other on clinical ground and the need for precise clinical-virological prospective studies in this susceptible population. References I. Aldrete, J. S., Sterling, W. A., Hathaway, B. M., et al.: Gastrointestinal and Hepatic Complications Affecting Patients with Renal Transplants. Am. J. Surg., 129:115, 1975. 2. Andersen, H. K. and Spencer, E. S.: Cytomegalovirus Infection Among Renal Allograft Recipients. Acta Med. Scand., 186:7, 1969. 3. Armstrong, D., Balakrishnan, S. L., Steger, L., et al.: Cyto-
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megalovirus Infections with Viremia Following Renal Transplantation. Arch. Int. Med., 127:111, 1971(a). 4. Aronoff, A., Gault, M. H., Huang, S. N., et al.: Hepatitis with Australia Antigenemia Following Renal Transplantation. Can. Med. Assoc. J., 108:43, 1973. 5. Back, J.-F. and Dardenne, M.: Serum Immunosuppressive Activity of Azathioprine in Normal Subjects and Patients with Liver Diseases. Proc. R. Soc. Med., 65:260, 1972. 6. Balfour, H. H., Jr., Groth, K. E., McCullough, J., et al.: Prevention or Modification of Varicella Using Zoster Immune Plasma. Am. J. Dis. Child., 131:693, 1977. 7. Berne, T. V., Chatterjee, S. N., Craig, J. R. and Payne, J. E.: Hepatic Dysfunction in Recipients of Renal Allografts. Surg. Gynecol. Obstet., 141:171, 1975. 8. Briggs, W. A., Lazarus, M. J., Birtch, A. G., et al.: Hepatitis Affecting Hemodialysis and Transplant Patients-its Consideration and Consequences. Arch. Int. Med., 132:21, 1973. 9. Chatterjee, S. N., Payne, J. E., Bischel, M. D., et al.: Successful Renal Transplantation in Patients Positive for Hepatitis B Antigen. N. Eng. J. Med., 291:62, 1974. 10. Conrad, M. E. and Knodell, R. G.: Viral Hepatitis (Commentary). J.A.M.A., 233:1277, 1975. 11. Craighead, J. E., Hanshaw, J. B. and Carpenter, C. B.: Cytomegalovirus Infection after Renal Allotransplantation. J.A.M.A., 201:725, 1967. 12. Eddleston, A. L. and Williams, R.: Inadequate Antibody Response to HBAg or Suppressor T-cell Defect in Development of Active Chronic Hepatitis. Lancet, 2:1543, 1974. 13. Fahrlander, H., Huber, F. and Gloor, F.: Intrahepatic Retention of Bile in Severe Bacterial Infections. Gastroenterology, 47: 590, 1964. 14. Freiberger, Z., Armras, G., Koff, R. S. and Bonney, W. W.: Chronic Active Hepatitis Without Hepatitis B Antigenemia in Renal Transplant Recipients. Gastroenterology, 66:1187, 1974. 15. Hathaway, W. E., Mull, M. M. and Pechet, G. S.: Disseminated Intravascular Coagulation in the Newborn. Pediatrics, 43:233, 1969. 16. Hill, R. B., Jr., Rowland, D. T., Jr. and Rifkind, D.: Infectious Pulmonary Disease in Patients Receiving Immunosuppressive Therapy for Organ Transplantation. N. Engl. J. Med., 271: 1021, 1964. 17. Hume, D. M., Lee, H. M., Williams, G. M., et al.: Discontinuation of Azathioprine with Maintenance of Renal Function. Ann. Surg., 164:352, 1966. 18. Ireland, P., Rashid, A., von Lichtenbery, F., et al.: Liver Disease in Kidney Transplant Patients Receiving Azathioprine. Arch. Intern. Med., 132:29, 1973. 19. Javitt, B. N.: Chronic Active Hepatitis. Am. J. Med., 55:733, 1973. 20. Klemola, E., Stenstrom, R. and von Essen, R.: Pneumonia as a Clinical Manifestation of CMV Infection in Previously Healthy Adults. Scand. J. Infect. Dis., 4:7, 1972. 21. Leinikki, P., Heinonen, K. and Pettay, O.: Incidence of Cytomegalovirus Infections in Early Childhood. Scand. J. Infect. Dis., 4:1, 1972. 22. Lee, J. C. and Fortuny, E. I.: Adult Herpes Simplex Hepatitis. Hum. Pathol. 3:277, 1972. 23.' Levine, A. R. and Ranek, L.: Asymptomatic Chronic Hepatitis -Correlations Between Isolated Serum Transaminase Abnormality and Liver Biopsy. Gastroenterology, 58:371, 1970. 24. Luby, J. P., Burnett, W., Hull, A. R., et al.: Relationship Between Cytomegalovirus and Hepatic Function Abnormalities in the Period after Renal Transplant. J. Int. Dis., 129:511, 1974. 25. Maddrey, W. C. and Boitnott, J. K.: Hepatitis Induced by Isoniazid and Methyldopa. Hospital Practice, 10: 119, 1975. 26. Millard, P. R., Herbertson, B. M., Evans, D. B. and Colne,
27. 28. 29. 30. 31.
32. 33. 34. 35. 36. 37.
38. 39. 40.
41.
42.
43. 44. 45. 46. 47.
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R. Y.: Azathioprine Hepatotoxicity in Renal Transplantation. Transplantation, 16:527, 1973. Miller, D. R., Hanshaw, J. B., O'Leary, D. S. and Huilicka, J. V.: Fatal Disseminated Herpes Simplex Virus Infection and Hemorrhage in the Neonate. J. Pediat., 76:409, 1970. Mitchell, J. R.: Drugs and the Liver. Viewpoints on Dig. Dis., 6(No. 5), 1974. Montgomerie, J. Z., Becroft, D. M. O., Crokson, M. C., et al.: Herpes-Simplex-Virus Infection after Renal Transplantation. Lancet, 11:867, 1969. Moore, T. C. and Hume, D. H.: The Period and Nature of Hazard in Clinical Renal Transplantation. Ann. Surg., 1970: 1, 1969. Nielsen, J. O., Dietrichson, O., Elling, P. and Christofferson, P.: Incidence and Meaning of Persistence of Australia Antigen in Patients with Acute Viral Hepatitis-Development of Chronic Hepatitis. N. Engl. J. Med., 285:1157, 1971. Nielsen, V., Clausen, E. and Ranek, L.: Liver Impairment During Hemodialysis and after Renal Transplantation. Acta Med. Scand., 197:229, 1975. Pirson, Y., Alexandre, G. P. and Ypersele, C.: Long-term effect of hbs Antigenemia on Patient Survival after Renal Transplantation. N. Engl. J. Med., 296:194, 1977. Pirson, Y., Van Ypersele de Strihou, C., Noel, I. I., et al.: Liver Disease in Transplanted Patients. Proc. Eur. Dial. Transplant Assoc., 10(0):434, 1973. Robinson, M. G. and Kaufman, S.: Disseminated Herpes Simplex, a Cause of Consumptive Coagulopathy. Soc. Ped. Res. Abstr. 103, 1969. Shons, A. R., Simmons, R. L., Kjellstrand, C. M., et al.: Renal Transplantation in Australia Antigenemia. Am. J. Surg., 128(5):699, 1974. Simmons, R. L., Kjellstrand, C. M. and Najarian, J. S.: Kidney transplantation: Technique, Complications and Results. In Najarian, J. S. and Simmons, R. L., eds., Transplantation. Philadelphia, Lea & Febiger, 1972, p. 445. Simmons, R. L., Lopez, C., Balfour, H., et al.: Cytomegalovirus: Clinical Virological Correlations in Renal Transplant Recipients. Ann. Surg. 180:623, 1974. Spencer, E. S.: Cytomegalovirus Antibody in Uremic Patients Prior to Renal Transplantation. Scand. J. Infect. Dis., 6:1, 1974. Spencer, E. S. and Anderson, H. K.: Clinically evident, nonterminal infections with herpes viruses and the wart virus in immunosuppressed renal allograft recipients. Br. Med. J. 3:251, 1970. Starzl, T. E., Marchioro, T. L., Porter, K. A., et al.: Factors Determining Short and Long-term Survival after Orthotopic Liver Homotransplantation. Surgery, 58:131, 1965. Torisu, M., Yokoyama, T., Amenisya, H., et al.: Immunosuppression, Liver Injury, Hepatitis in Renal, Hepatic and Cardiac Homograft Recipients: with Particular Reference to Australia Antigen. Ann. Surg., 174:620, 1971. Vittal, B. S., Thomas, W., Jr. and Clowdus, B. F.: Acute viral hepatitis-Course and Incidence of Progression to Chronic Hepatitis. Am. J. Med., 55:757, 1973. Vermillion, S. E., Gregg, J. A., Baggenstoss, A. H. and Bartholomew, L. G.: Jaundice Associated with Bacteremia. Arch. Int. Med., 124:611, 1969. Ware, A. J., Luby, J. P., Eigenbrodt, E. H., et al.: Spectrum of Liver Disease in Renal Transplant Recipients. Gastroenterology, 68:755, 1975. Whelan, G. and Sherlock, S.: Immunosuppressive Activity in Patients with Active Chronic Hepatitis and Primary Biliary Cirrhosis Treated with Azathioprine. Gut, 13:907, 1972. Zarday, A., Veith, F.-J., Gliedman, M. L. and Soberman, R.: Irreversible Liver Damage after Azathioprine. J.A.M.A., 222: 690, 1972.
