Liver
Dysfunction
in Children
and
Adolescents
During
Hemodialysis
and
After
Renal
Transplantation
Robert
S. Fennell
III,
MD, Joel M. Andres, MD, William W. Pfaff, MD,and George A. Richard, MD
From the Divisions of Pediatric Nephrology and Gastroenterology, Department of Pediatrics, and Division of Transplantation Surgery, Department of Surgery, University of Florida College of Medicine and Shands Teaching Hospital, Gainesville
ABSTRACT. Liver dysfunction is common in patients on
hemodialysis or during the posttransplant period. Twelve
children in the End-Stage Renal Disease Program at the
University of Florida ranging in age from 4 to 18 years,
developed persistent, elevated liver enzymes (SGOT or SGPT > 100 lU/liter) during hemodialysis in preparation for renal transplantation. Eleven of 12 developed enzyme elevations within six weeks of the initiation of
hemodi-alysis. The other child exhibited enzyme elevations after one year on dialysis while awaiting a second transplant. Most of the children were anicteric and asymptomatic.
Potential hepatotoxic drugs were discontinued when
Se-rum transaminase elevations were noted. Hepatitis B
surface antigenemia was associated with enzyme
eleva-tions in one patient; cytomegalovirus seroconversion had occurred in eight patients, but only three had associated
enzyme
elevations. Liver biopsies were performed in allthe patients before or at the time ofrenal transplantation.
The histology was variable and ranged from normal in
six patients, mildly abnormal with changes compatible with acute hepatitis in four patients, and granulomatous
hepatitis in one patient, to severely abnormal with
chronic hepatitis in the remaining patient. Seven of the
12 children underwent successful transplantation with
return of enzyme levels to normal in five and persistent
elevations in the others. These fmdings suggest that
evaluation of liver histology provides the only accurate
means of assessment of persistent liver dysfunction in
children and adolescents on hemodialysis and after renal transplantation. Pediatrics 67:855-861, 1981; liver dys-function, renal disease, hemodialysis, transplantation.
Hepatic dysfunction has been reported in
pa-tients with chronic uremia during repetitive
hemo-Received for publication Nov 7, 1979; accepted Oct 24, 1980. Reprint requests to (J.M.A.) Pediatric Gastroenterology, Box J-296 JHMHC, University of Florida College of Medicine,
Gaines-ville, FL32610.
PEDIATRICS (ISSN 0031 4005). Copyright © 1981 by the
American Academy of Pediatrics.
dialysis’3 and after kidney transplantation.46 These patients with significant elevations in serum transaminase levels are usually asymptomatic and
examination of their liver histology often reveals
only mild nonspecific hepatitis.7 More severe liver abnormalities occur, however, which are difficult to predict by clinical or biochemical criteria.5 In addi-tion, a specific etiology may not be apparent al-though various hepatotoxic viruses5’8’9 and drugs6
have been causally related to the liver dysfunction. There is little information in the pediatric literature that describes the longitudinal progression of liver abnormalities in children with renal insufficiency who require hemodialysis and transplantation. We report our experience with children and adolescents who exhibited serum transaminase level elevations while undergoing hemodialysis, and review their subsequent clinical course during the posttrans-plant period.
SUBJECTS AND METHODS
The clinical course, laboratory data, and liver histologic fmdings were reviewed for 12 children who exhibited significant and persistent liver dys-function while undergoing hemodialysis. Liver dys-function was defined as an elevation in levels of
serum
glutamic oxaloacetic transaminase (SGOT)and serum glutamic pyruvic transaminase (SGPT) greater than 100 IU for at least two consecutive months. Serum SGOT and SGPT levels were de-termined by the autoanalyzer method of Kessler et al.’#{176}Hepatitis B surface antigen (HB,,Ag) and anti-body (anti-HB8) determinations by
p, Ag, S..
S (‘sf... (Is,
F C U,.. s,y p,,.5 2 A 0 S Is S C ppIs 3 A 4 S Is S C p,No 4 S Is ,I C p,No S A I? S F R ,sS p,N. 6 A 6 S N S C DIys) 1500T,SGPT 300) .=14,th) = IT.) ICMV) 50) ))PAQ-N.g) 4B.-M) - _)) )SGOT/SCPT 450) [ lASs,) - [ )T.)
#{163}MV132) Is,. U3ys) T/SGPT500) u433T/%PT 300) ‘ (AzAS (M.thl
S9i,=:::=:= (CMVI(251
He, Ag-Nw L5)1ASSs 555Is1’& -I..”) )SG0T403GPT 700) 4(8.-N. I #{149}(0I,)
I)SGOT 3OWSGPT 200) _____(CMV) 32) )sAq NQ) us,.... F Il0(,sl #{149})SGOT/$GPT200) 1 (M.ftl) 4CMV-N.o) )(s, Ag-TAg) 66.61)
40 50 60 70
YEARS
Fig 1. Clinical course (in years) of renal failure patients
with normal liver biopsies despite abnormal liver func-tion. All abbreviations are noted except: F, female; M,
male; C, white; Orient, oriental; NL, normal; Neg, nega-tive; completed course; c, ongoing course.
the 12 children (hepatitis B e antigen [HBeAg] and e antibody [anti-HBe] were not determined because these tests were not available). Measurements of serum transaminase levels were obtained within one month prior to the initiation of hemoclialysis and subsequently at monthly intervals. Antibody to
cytomegalovirus
(CMV) was measured bycomple-ment fixation prior to initiation of hemodialysis and this test was repeated if clinical or laboratory evi-dence of hepatitis was noted during hemodialysis or in the posttransplantation period. CMV serocon-version was defined as a fourfold or greater increase in titer of antibody. Cultures for CMV were not done. When indicated, the
immunofluorescent-an-tibody slide test for Epstein-Barr viral capsid anti-gen was also performed.9
There were eight boys and four girls, ranging in age from 4 to 18 years with a median age of 10
years,
who exhibited elevated serum transaminaselevels. End-stage renal disease was secondary to
glomerulonephritis in five patients, dysplastic kid-neys in four patients, obstructive uropathy with pyelonephritis in two patients, and congenital ox-alosis in one patient. The 12 patients were part of a larger group of 121 children and adolescents ad-mitted to the University of Florida Hemodialysis and Transplant Program from 1972 to 1978. None of the other 109 patients had significant serum
transaminase
level elevations (greater than 100 IU)for any sustained period of time (two consecutive months). Antihypertensive drugs were used only when blood pressure elevation could not be con-trolled by ultraffitration during hemodialysis, in conjunction with fluid and salt restriction. The pa-tients underwent a percutaneous liver biopsy while on repetitive hemodialysis (five patients), or an open liver biopsy at the time of surgery for bilateral nephrectomy (five patients) and kidney transplan-tation (two patients). Liver specimens were placed in routine fixatives and stained with hematoxylin and eosin, Masson trichrome, and silver methena-mine.
Thirteen kidney transplants were performed in
ten of the 12 patients. Living related donors were used as allograft sources in seven patients and ca-daveric donors were used in six. In the patients who received transplants and developed severe allograft rejections during hemodialysis reduced doses of azathioprine were continued until recovery of graft function was determined to be improbable.
RESULTS
Significant morbidity or mortality did not occur after liver biopsy in any patient. One child became transiently hypotensive without a decrease in he-matocrit level, and responded to treatment with
intravenous fluids. The clinical data of each patient
are sequentially ifiustrated in Figs 1 and 2. Significant alteration of chemical liver function
occurred
within
eight weeks of the initiation ofhemodialysis in 11 ofthe 12 patients. In the remain-ing patient, liver dysfunction was noted approxi-mately one year after the onset of dialysis therapy. Some of the patients ingested potentially
hepato-toxic
drugs within one year of the observed serumtransaminase level elevations; these drugs are listed and duration of use and temporal relationship to the development of hepatic dysfunction are also
shown (Figs 1 and 2). With the exception of patients 12 and 2 who were receiving azathioprine (Imuran,
Burroughs-Wellcome Co, Research Triangle Park,
NC) for three years and one year, respectively, administration of potentially hepatotoxic drugs was started within two weeks of the onset of dialysis. In these two patients, however, azathioprine was dis-continued 12 months and one month prior to serum transaminase level elevations. The other major he-patotoxic drug, methyldopa (Aldomet,
Merck-Sharpe
and Dohme Co, West Point, PA), was givento four patients. Approximately 40% of our 121 hemodialyzed patients required an antihyperten-sive drug; methyldopa was used in 50% of these
individuals. Hence, the 12 patients with persistent
sam-Aq
SR.
7 DsAy1T S E”Y” #{163}6.
F Azo6oITze TAg L’ B.zpTy PINY 0 A 8 S 8 8 8 PINA 9 A 2 S 8 S 8 190Y C A 3 S 8 A 8 A 0 S Is A C (ST.) 2 S F 0 8 - (0(T 320T5O0,SGPT 000) :: o::___::: (T.) (CMV TAg) (A8 AgNeg) ))NACA1 P*p6lY-zYpRzRd) . c::::
000T 500,SGPT 400) #{149}(T.
NegE::ITi: CMV ) 250)
MARsAg-TAg) ((ACAIR hepzlds) )%Q/53PT 300)
_ 45001,SCPT 400)
U #{149})A0h)
)Neq) Li CMV I250)
(YBs A-NeqJ
)SCOT, SCOT 00) -i:i: j_::)CP.4v) 64)
(500R h,pott) #{149}(D)ys) #{149}csooi/sc,PT 300)
1:-i---iiIii )AzlT)
1)981 Ag-FAg AYl18 P) )(Go’sAOR’0’Ol4 hepohts)
U L...(D),s
(SOOT, 3601 300w )SG0T/SGPT 000) #{149})Azth
#{149}(T.
:TT-:---
--
---
--
-
-
-
(CMVI 28)(88, Ag-TAg)
ICfrOYIC s6SRosc
hepoht,s-6ep0109 .“p’ozed) DO 0 20 30 40 50 60 70 75
YE4RS
Fig 2. Clinical course (in years) of renal failure patients with abnormal liver biopsies and liver dysfunction. All abbreviations are noted except: F, female; M, male; C, white; B, black; Pos, positive; Neg, negative; ,
corn-pleted course; D, ongoing course.
ple of the entire group of renal failure patients treated with potential hepatotoxic drugs.
The liver biopsy of each child with renal insuffi-ciency was reviewed and patients were divided into normal or abnormal groups based on the histologic findings. There were six children (Fig 1) with nor-mal hepatic architecture, although serum transam-inase levels (SGOT and SGPT) ranged from 100 to
800 IU for periods of two to 14 months. No patient in this group was positive for HBs,Ag, anti-HB5, or anti-HB (four of the six tested for core antibody).
Three out of the six (patients 1, 2, and 5) had
positive CMV titers prior to hemodialysis and be-fore the onset of serum transaminase level eleva-tions. Three children (patients 3, 4, and 6) required treatment with methyldopa for two to eight weeks; the drug was discontinued in all three patients prior to or within two weeks of detecting serum
trans-aminase level elevations. One child (patient 2) had
received azathioprine for one year following his initial kidney transplantation. In this patient, the SGOT and SGPT levels increased one month after rejection of the first transplant, the discontinuance of azathioprine, and the initiation of the second course of hemodialysis. Five of the six patients
underwent renal transplantation and now have had
functioning renal allografts for six months to three years; liver enzymes had returned to normal prior
to transplantation in all but patient 2 whose serum
transaminase levels returned to normal over the
course of one year after successful kidney trans-plantation. Four weeks after transplantation one child (patient 3) experienced a threatened allograft rejection manifested by a brief episode of fever and leukopenia. In addition, CMV seroconversion oc-curred at this same time with hepatomegaly and serum transaminase level elevations ranging from 300 to 400 IU. A liver biopsy was repeated and the
histology was consistent with acute viral hepatitis
although CMV inclusions were not noted. The pa-tient recovered uneventfully and liver enzymes
re-turned to normal six weeks after he received the
renal allograft. Patient 4 died suddenly at home two weeks prior to scheduled transplantation. His death occurred ten weeks after the liver biopsy and four weeks after normalization of serum transaminase levels. Permission for necropsy was denied by the family.
Fig 2 represents the six children with abnormal liver biopsies. There were four patients (nos. 7 to 10) with acute hepatitis at the time of their initial biopsies and biochemical evidence of hepatic dys-function with serum transaminase levels ranging from 200 to 1,000 IU. None of these children had signs of liver disease. Two patients had lymphocytic infiltration throughout the hepatic lobule and in portal tracts, along with scattered foci of liver cell necrosis and Kupifer cell hyperplasia. The others
had only mild lymphocyte infiltration of portal
tracts or “triaditis” (Fig 3); one of these patients (no. 10) became positive for HBAg two months prior to the initiation of hemodialysis and before the administration of any known blood products. He was the only patient in the study with positive HBAg serology (and anti-HB), and subsequently developed clinical signs and symptoms of liver dys-function consisting of hepatomegaly and right up-per quadrant tenderness. The elevation of serum
transamina$e levels persisted for seven months
after the cessation of symptoms and the initiation of repetitive hemodialysis.
Patients 8 and 9 developed serum transaminase level elevations four to eight weeks after renal trans-plantation while they were receiving azathioprine.
Each was exhibiting severe allograft rejections with
cessation of renal function requiring maintenance hemodialysis. Also, there was an associated CMV
infection
as
evidenced by a fourfold rise in serologictiters
to
levels greater than 1:250. Typical viralinclusion bodies were not discovered in either of these liver biopsy specimens. Both patients
even-tually lost their allografts. Patient 7 developed
se-rum transaminase level elevations while receiving
Fig 3. Liver section showing mild mononuclear cell infiltrate in portal tract (“triaditis”)
with minimal lobular inflammation (hematoxylin-eosin, x100).
Fig 4. Mild mononuclear cell infiltrate involving hepatic lobule with granuloma adjacent
to portal tract (hematoxylin-eosin, x100); Inset: detailed enlargement of noncaseating granuloma (x250).
occurred one month after the initiation of
hemodi-alysis and persisted for six months after
discontin-uance of methyldopa and the other drugs. Success-ful bilateral nephrectomies controlled hypertension. Subsequently, she underwent successful renal allo-graft transplantation from a living related donor and did not have any further clinical or chemical
signs of hepatic disease. Normal liver histology was
noted for patient 1 1 except for mild lobular
lym-phocytic infiltration and the additional finding of
hepatic granulomas (Fig 4). Serum transaminase levels were as high as 300 IU one month after the
initiation
of
hemodialysis and persisted for twoof the liver tissue for acid-fast bacilli was negative. Skin tests for tuberculosis and histoplasmosis were nonreactive (a Kveim test was not placed) and chest
films were negative for pulmonary disease and hilar
adenopathy. The patient exhibited skin reactivity
to Candida and Trichophyton antigens. Serology
for Epstein-Barr virus and CMV was also negative. The patient had not ingested sulfonamides, clofi-brate, or beryllium and the stool was negative for parasites. Before the initiation of hemodialysis, however, he was noted to have anti-HB8. There was no past history of hepatitis B virus disease or known liver dysfunction, although at an earlier age the family was told the child’s liver was enlarged.
Suc-cessful transplantation was subsequently performed
in this patient without complications; the renal allograft has been functioning for longer than 12 months without any evidence of rejection and liver
enzymes
have remained normal. Isoniazid was notused prophylactically.
Patient 12 with chronic hepatitis developed ele-vated serum transaminase levels ranging from 200
to 400 IU after repetitive hemodialysis for 12 months, and the liver dysfunction persisted for an additional ten months while she was on dialysis awaiting a second renal transplant. Azathioprine, which she received for three years following her initial renal transplant before loss of graft function due to chronic rejection, was discontinued 12 months prior to liver dysfunction. A liver biopsy was performed at the time of her second transplant when serum transaminase levels had been normal
for two months. However, the histologic diagnosis was chronic active hepatitis because of bridging fibrosis and patchy liver cell necrosis with periportal mononuclear infiltrates, in addition to increased fibrous tissue in the portal tracts (Fig 5). She ex-hibited no clinical or laboratory evidence for
a,-antitrypsin deficiency or Wilson’s disease. Antinu-clear, antimitochondrial, and antismooth muscle antibodies were negative and serum complement was normal. She was repeatedly negative for HBAg and anti-HB8. Her second posttransplant period was complicated by two upper gastrointestinal tract bleeding episodes which eventually required vagot-omy and pyloroplasty. At this time, she developed signs of acute hepatitis with an increase in serum transaminase levels to 1,000 IU, jaundice, hepato-megaly, and upper right quadrant tenderness. This acute episode eventually subsided after the admin-istration of higher doses of prednisone, and the substitution of cyclophosphamide for azathioprine. The liver enzymes gradually returned to normal
after nine months of prednisone therapy. Liver
his-tology improved with a decrease in hepatic cell necrosis and mononuclear infiltrates despite ongo-ing repetitive hemodialysis because of allograft re-jection.
DISCUSSION
The significance of abnormal serum transaminase
levels and histologic evidence of hepatic injury in
renal patients during hemodialysis and after
trans-Fig 5. Mild portal tract infiltrate with patchy liver cell necrosis and early bridging
plantation is difficult to assess. Ware et al5 de-scribed 31 of 82 adult renal transplant recipienth with liver dysfunction. Of these patients, 25 devel-oped hepatic complications within six months of transplantation and eight had anicteric, reversible disease associated with CMV seroconversion, a!-though a causal relationship between CMV and liver disease after renal transplant could not be proven. In this same study, two patients had acute liver failure and 21 developed chronic liver disease
by history or documentation with liver biopsy. In
contrast,
Malekzadeh et a!6 described only one ofnine pediatric renal transplant recipients with
pos-itive serology for CMV and others2 have not been able to demonstrate seroconversion in their
pa-tients.
In the present study, eight of 12 patients hadserologic evidence for infection with CMV (39% of all our renal transplant patients demonstrated a
rise in CMV titers1’). However, only three of the eight developed liver dysfunction associated with the seroconversion, and each of the three patients recently had had transplants and were receiving large doses of immunosuppressive drugs.
Addition-ally, two of these three patients experienced
irre-versible allograft rejection; both patients had ab-normal liver histology and delayed resolution of hepatocellular dysfunction. The other patient with possible CMV disease had normal liver histology six months before seroconversion and then
devel-oped acute hepatitis following his transplantation,
He experienced a mild, reversible rejection episode and a brief delay in the return of normal liver function. All patients with a normal liver biopsy, who underwent surgery, had successful renal trans-plantation. In addition, the children without a
his-tory of acute CMV seroconversion iuaintained nor-mal liver function after their first transplantation. For six of the ten
patients
with transplants serumtransaminase levels returned to normal prior to or
at the time of renal allograft acceptance, but it is noteworthy that the patients with a history of re-peat kidney transplantation also experienced delay
in resolution of abnormal liver function. Assessment of the above information and formulation of definite
conclusions is difficult because of the small size of our study population. However, it appears that
abnormal liver histology, perhaps related to CMV infection, may predispose the renal failure patient to allograft rejection and prolonged liver dysfunc-tion, especially if there has been a history of repeat
kidney transplantation. Furthermore, our data
sug-gest that children undergoing repetitive
hemodi-alysis are at greater risk to develop hepatocellular dysfunction than if they receive a successful renal
allograft.
Other viruses, especially hepatitis B, have caused liver dysfunction in renal failure patients. In fact,
the presence of HBs,Ag in the serum has been as-sociat,ed with the duration of hemodialysi.s,8”2 Hep-atitis B virus did not play a major role in our patients; only one patient was positive for HB,Ag
with associated liver enzyme elevations arid
histo-logic evidence for cellular infiltration of portal tracts. One other patient with anti-HB8 antibodies apparently had a previous episode of hepatitis B
surface antigenemia. This was noted prior to the
development of renal failure and has had no dele-terious effect on allograft survival. Lack of response to HB,Ag in renal failure patients often results in an asymptomatic carrier state and, in some
pa-tients,
may lead to enhanced graft survival aftertransplantation.’3’14 Other studies,’5”8 however, have demonstrated no long-term advantage for
pa-tients
with a lack of response to HBIIAg. Patientswith end-stage renal disease, who respond to HBAg by producing significant anti-HB5 titers, have been
reported’3”7 to mount vigorous allograft rejection
resulting in decreased graft survival. Epstein-Barr virus has been reported9 to cause hepatitis in the
patient after renal transplantation; however, sig-nfficant liver disease may be limited to hemodialysis patients, Hepatitis A virus is of little importance in hemodialysis or posttransfusion hepatitis,’2”8 and there is no way to identify other putative viruses such as non-A or non-B.’9
An association has been noted between hepatic dysfunction and azathioprine therapy in the post-transplant period.6 Hepatotoxic drugs were used in eight of our patients; four required administration of methyldopa for severe hypertension and the re-maining patients were inmunosuppressed with aza-thioprine after renal transplantation. We were un-able to establish clearly evidence for drug-related liver dysfunction
in
any of these patients. In fact,the
serum
transaminae
level elevations persistedin a few patients for months after discontinuance of the potentially hepatotoxic drug. Moreover, serum
tranaamiiase levels remained normal or promptly returned to nprn’ial in four patients when azathio-prine was begun ip the immediate posttransplant
period. Our observations may differ from those of
Malekzadeh et al,6 who discovered a close
associa-tion between liver dysfunction and treatment with
azathioprine, because we evaluated patients during
hemodialysis prior to transplantation, as well as in the posttranspl.ant period.
There may be other, less well defined causes for liver dysfunction in patients with chronic uremia. Mattenheimer et al’ described the unusual histo-logic findings of focal hepatic anoxic changes in hemodialyzed patients and this was attributed to
sludging of red blood cells. Liver damage has been
associated with the release of products such
as
chloride tubes used with hemodialysis equip-ment.#{176}’2’ Others have suggested that the high inci-dence of hepatitis in dialysis units is related to deranged metabolism and nutritional impairment of the liver in renal failure,22 or altered immunologic
responsiveness of the uremic host.’
All
12 patients who underwent transplantation and/or hemodialysis had normal liver function at the end of our study. However, at some time during their observation period, six of the 12 children had biochemical liver dysfunction and normal liver his-tology. These patients could not be distinguished from the children with liver histologic changes com-patible with acute and chronic liver disease. We suggest, therefore, that histologic evaluation of liver tissue be considered for all hemodialyzed and renal transplant patients who have persistent liver dys-function, especially if they had a previous kidney allograft and are awaiting a repeat transplant, and there has been a change in CMV serologic status. In this situation, we believe that it would be prudent to delay transplantation surgery especially if the liver histology proved to be abnormal. Otherrec-ommendations cannot be made regarding the
po-tential risk of surgery in the child with renal failure; however, hepatocellular dysfunction should at least be resolving in these patients before any type of surgery is contemplated.24
It is important to emphasize that liver histology
cannot
be reliably predicted by the usual clinicaland biochemical criteria in patients undergoing re-petitive hemodialysis and renal transplantation.
Also, significant liver histopathology, eg,
progres-sive hepatic fibrosis, may occur in these patients and is potentially amenable to specific therapy.25 Evaluation of liver histology, therefore, provides the only accurate means of assessment of liver dysfunction in children and adolescents with chronic renal failure.
ACKNOWLEDGMENT
We are indebted to Dr Perry Teague for the radioim-munoassay determinations of anti-HB.
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