REVIEW

Liver Disease in Renal Transplant Recipients

JOSEPH SOPKO, M.D. SINN ANURAS,

M.D.

lowa City, lowa

From the Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa. Requests for reprints should be addressed to Dr. Sinn Anuras, Department of Medicine,. University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242. Manuscript accepted July 15, 1977.

Liver disease is a common complication in renal transplant recipients. Several types of liver disease can occur. The most common are acute and chronic hepatitis. The variety of acute hepatitis include hepatitis A, hepatitis 6, cytomegalovirus hepatitis, herpes simplex hepatitis and azathioprine hepatitis. The incidence of azathioprine hepatitis may not be as high as initially suggested. Chronic hepatitis is a serious problem because the disease seems to be progressive despite prednisone therapy. The causes of this chronic hepatitis are not fully known, although hepatitis B, cytomegalovirus and herpes simplex virus have been implicated. Discontinuation of azathioprlne therapy has no appreciable effect on the course of chronic hepatitis. The immunosuppressed patient (patient receiving immunosuppressants) is at increased risk of infection and, to date, this has contributed in a significant way to the morbidity and mortality of this group [ 11. The renal transplant patient shares in this experience [2]. Indeed, this represents the major etiology of death [3-61. Eickhoff [7] reports that 60 per cent of a group of renal transplant recipients had bacterial infections, 20 per cent had fungal, 26 per cent had viral and 5 per cent had pneumocystis carinii infections. Although unusual infections have been stressed by some investigators, a high prevalence of hepatic dysfunction has been noted from the earliest days of renal transplantation [8-lo]. Forms of liver disease reported include hepatitis A, hepatitis B, cytomegalovirus hepatitis, herpes simplex virus hepatitis, Varicella-Zoster hepatitis, azathioprine hepatitis, hepatoma, intrahepatic cholestasis and hepatic veno-occlusive disease. Each of these entities will be reviewed. The initial case reports and reviews, lacking modern serologic studies, could only speculate as to etiology. Of the 45 patients who received transplants between 1959 and 1963 at the Necker Hospital, five became jaundiced, and one died. It was assumed that either azathioprine or 6-mercaptopurine was the etiologic agent [ 111. In their review of 1968, the Cambridge University group reported that five of 49 renal homotransplant recipients died of hepatitis. They noted that the morphologic features were not those of infectious hepatitis or cytomegaldvirus in that there was no substantial inflammatory cell infiltrate. Abnormal liver functions were noted from one to 49 days after renal transplantation [ 121. The initial American experience was published by three groups in 1969. Moore and Hume [ 131 reported that five of their 113 recipients had hepatitis 60 days to 54 months after they received their transplant. Sixty-seven per cent of these occurred within 60 to 108 days after surgery. This complication was twice as

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common in recipients of cadaver kidneys when compared to recipients of kidneys from related living donor. of the five recipients of related living donor kidneys who had hepatitis, four survived and one died. In the recipients of cadaver kidneys, however, 50 per cent of the patients died from hepatitis. Penn et al. [ 141 reported that 88 of 146 of their transplant recipients had abnormal liver function tests. In a majority, this occurred within the first six months of transplantation. The abnormalities were transient and mild in 66 of the 88 cases. The same investigators speculated that either viral hepatitis, immunosuppressive or other drugs were the cause. Reeve et al. [ 151 described a 6 per cent incidence of hepatitis in a series of 95 renal transplant recipients. Time of onset was not reported. These early series were before the general availability of a means of testing for the hepatitis B antigen. More recently, available serologic studies have allowed a greater insight into the cause of liver disease in renal transplant recipients. Acute Viral Hepatitis (Hepatitis A and Hepatitis B). The hepatitis B problem in the renal transplant group is an extension of that among patients undergoing hemodialysis. The presence of the hepatitis B surface antigen (HB,Ag) has been closely related to the number of transfusions and hemodialyses [ 161. Others, however, have argued that the adjusted prevalence rates are more strongly correlated with the duration of dialysis than with the number of transfusions [ 17,181. It has been generally observed that the clinical and laboratory features of hepatitis B in patients undergoing hemodialysis and in staff members of these units were different [ 191. The patients tended to manifest a chronic, anicteric disease with serum glutamic pyruvic transaminase (SGPT) levels under 1,000 Karmen units, but elevated SGPT levels lasted for 20 weeks or more [ 20]_ This is consistent with immunologically deficient patients who usually have a mild, anicteric hepatitis [ 2 1] . The staff, on the other hand, experienced an acute disease characterized by serum bilirubin levels greater than 3 mg/ 100 ml, SGPT greater than 1,000 U and duration of elevated SGPT levels of less than 10 weeks. A Center for Disease Control survey of hemodialysis units revealed an incidence of viral hepatitis in patients and staffs of 4.4 cases per hundred at risk [22]. Diagnostic criteria for hepatitis varied from section to section. Almost 70 per cent of the patients were anicteric, whereas 85 per cent of the staff members were jaundiced and 74 per cent were ill enough to require hospitalization. Viral hepatitis as defined by a threefold or greater increase in SGOT or a lesser increase associated with the development of an antigenemia in the renal transplant patient (53 per cent positive HB,Ag in one center)

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is perhaps even milder. This is true whether the criterion is the level of bilirubin or SGDT, severity of symptoms, duration of elevated SGOT level or mortality 1231. It would seem then that the major risk of viral hepatitis in this group is that of transmissions to healthy staff members (20 per cent mortality in one series) [5,23-281. In about half of those affected the clinical picture of acute hepatitis, elevated transaminase levels, anorexia, fatigue and fever, tends to occur from two to 14 months after renal transplantation [ 181. The others manifested a more insidious onset whose chief symptom was usually fatigue. In those patients studied for HB,Ag, hepatitis was clinically manifest from one to 11 months after the HB,Ag was first noted. The mortality from liver disease was approximately 25 per cent [ 181. In a prospective study in which HB,Ag testing was performed by counterimmunoelectrophoresis every three months, approximately 13 per cent of the renal allograft recipients had hepatic dysfunction; in only 17 per cent of these was it HBsAg positive [29]. The onset of biochemical hepatitis was 18 months after transplantation, with a range of one to 30 months. In those patients who have HB,Ag after receiving a renal transplant the risk of clinical hepatitis developing is approximately 15 per cent [30]. Viewed differently, the frequency of hepatic dysfunction is approximately the same, whether a patient has HB,Ag or not [3 11. Cytomegalovirus (WV) Hepatitis. The cytomegalovirus was first isolated in 1956 [32,33]. Since that time a variety of common infections have been attributed to this agent, especially those occurring in the immunologically deficient state [34-361. Hepatic involvement has been noted commonly in congenital CMV infection [37-391, in postnatal CMV infection [40,41], in CMV mononucleosis [42,43], in CMV hepatitis in the adult [40,44], in granulomatous hepatitis [45] and in postperfusion CMV infection

[4’31. The clinical features of hepatitis associated with CMV seroconversion in the post-transplant patient are similar to CMV hepatitis which occurs in other settings, especially in CMV mononucleosis [47-481. In many patients, however, a syndrome of an acute febrile illness with temperatures up to 106OC has been reported [49]. When studied prospectively, culture documented (in many cases) hepatitis developed two to three months after transplantation [47,49-531. These studies also show that the onset of hepatitis is closely associated with CMV seroconversion, defined as a fourfold or greater increase in complement fixation antibody. An increase in the CMV titer appears to be a measurement by which the occurrence of hepatitis can be predicted. Hepatitis developed in 21 per cent of those whose titer increased 0 to 3 times as opposed to 67 per cent of

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those whose titer increased 4 to 8 times and 100 per cent of those whose titer increased 8 times or more [47]. Further, CMV seroconversion is associated with culture documented isolation in 87 per cent [54]. Viral isolation generally occurred four days prior to seroconversion. Thus, the latter appears to be a better indicator of the onset of infection [54]. The over-all infection rate as measured by seroconversion appears to be close to 70 per cent and is even higher for patients with elevated CMV titers prior to transplantation [47,50]. Rates as high as 90 per cent have been reported [29,55]. A clear etiologic factor appears to be blood transfusion, especially more than 20 U; duration of prior dialysis does not appear to be significant [50,56]. Whether whole or fresh blood was used does not appear to affect the frequency of CMV infections [57]. Additionally, l-lo et al. [50] demonstrated a correlation between the serum CMV titer of the donor and the development of infection. Of 12 patients with negative serum CMV titers who received kidneys from donors whose serum CMV titers were positive, 10 became infected; only three of 10 who received kidneys from donors whose serum CMV titers were negative became infected [50]. However, the virus has not been isolated from a transplanted kidney [58]. Thus infection may be secondary to subclinically infected or carrier donors [59]. Also, there may be reactivation of endogenous infection since the infection rate in the prior to transplant seropositive group has been reported as high as 90 per cent versus approximately 40 per cent in those who were seronegative prior to transplantation [50,60,61]. Indeed, in one series, this appeared to be the primary source [52]. Duration of CMV hepatic dysfunction ranges from one to 20 weeks with excellent prognosis and without recurrence at up to three years follow-up [49,59]. Cytosine arabinoside has been suggested as therapy in severe cases, but a controlled trial has not been made [ 53,621. However, to what extent CMV is a contributing cause in those patients who die is not clear. Morphologic or cultural evidence of infection has been found in 30 to 50 per cent of patients who die after renal transplantation [36,52,63]. Azathioprine Hepatitis. Azathioprine is an imidazole derivative of 6-mercaptopurine. The latter has been reported to cause hepatic dysfunction in leukemic patients which generally cleared with cessation of therapy [64]. A similar picture has been described in nonleukemic patients [65,66]. Approximately half of those who became jaundiced did so within the first 60 days of treatment [65]. Systemic indications of hypersensitivity; rash, arthralgias, eosinophilia were not observed. Further, in those cases in which therapy with the drug was reinstituted, the latent period was not

markedly shortened. All of this has been interpreted as pointing to a direct toxic effect. Experimental studies have shown azathioprine to be hepatotoxic in canine models, usually in the dose of 2 to 4 mg/kg [67-691. In dogs, transaminase and alkaline phosphatase levels rise sharply in a few days of administration of the drug: they tend to regress in some, but in one third centrilobular damage or necrosis resulted. Mortality was 33 per cent [67]. A similar cholestatic picture on biopsy has been repotted in the post-renal transplant patient group [70]. In renal transplant patients, azathioprine has been reported to cause hepatic dysfunction from 30 to 900 days post-transplant [71-731. Frequently abnormalities abated after the dosage was lowered or administration of the drug was discontinued [24,29,71]. Reinstitution of the drug is reported to cause exacerbation of hepatic dysfunction in over 50 per cent of patients [23]. Fairly strong contradictory data exist, however. In a series of 50 consecutive renal transplant patients, liver functions were measured weekly. The SGPT levels were grouped according to whether an increased or decreased average weekly dose of azathioprine had previously been received. The groups were also matched on the basis of renal function since this, perhaps, would influence hepatotoxicity. None of these patients had HB,Ag. It was noted that increased SGPT levels were just as likely to be related to increased azathioprine doses as to decreased doses. The degree of damage seen in liver histology in those patients who died was not related to the dose of azathioprine over the two months prior to death [74]. Luby et al. [47] blindly matched 11 patients with HB,Ag negative hepatitis with control subjects by age, sex, race in the study group in whom hepatitis did not develop. The mean azathioprine dose at the onset of hepatitis was 1.97 mg/kg/day. For the control subjects it was 1.92 mglkgfday. Millard et al. [63] reported that none of their renal transplant patients with focal hepatic necrosis at death were receiving large doses of azathioprine and that 12 of the 17 patients with that lesion were either receiving minimal doses or none at all. Ireland et al. [75] found that clinical or laboratory evidence of liver disease developed in 13 per cent of the 196 renal transplant patients treated with azathioprine. They divided these patients into three groups. In group I, liver disease paralleled episodes of sepsis in onset, severity and duration. All died. Azathioprine therapy did not appear to affect the course of their illness. The illness in five of seven diminished despite continued therapy, worsened after azathioprine therapy was discontinued or diminished after rechallenge. In one patient, the disease was unchanged when administration of the drug was discontinued; in another, disease

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progressed during azathioprine therapy. Group II consisted of 12 patients with viral hepatitis, half had HB,Ag. Three of these patients died. The discontinuation of azathioprine therapy had no effect upon the course of the illness. In eight patients the liver disease diminished with azathioprine therapy, became more severe upon its discontinuation or diminished with rechallenge. One patient was not rechallenged due to his rapid remission. Group III consisted of patients in whom the etiology of the hepatic dysfunction was less clear; the clinical picture was not typical of viral hepatitis. In four patients, the liver disease was not related to azathioprine therapy. In the fifth patient, it was administered until three days before death. Liver biopsies, anti- or postmortem, in all three groups of patients failed to show a consistent pattern of injury between the groups that could be common to a single etiologic agent. These investigators concluded that liver disease is not an indication to discontinue azathioprine therapy. It remains possible that azathioprine may predispose to the development or worsen the sequelae of intercurrent hepatitis of any cause, but especially of an infectious agent. Herpes Simplex Virus (HSV) Hepatitis. In the adults, HSV was first reported as an etiologic agent for fulminant hepatitis in 1969 [76,77]. Since that time approximately 10 more cases have been reported [78-861. Only one of these patients survived [77]. In most of the patients, immunosuppression had been achieved or they had severe underlying illnesses. These included Hodgkin’s disease, thymic dysplasia, burns, pregnancy, celiac disease, steroid-treated pemphigus vulgaris and asthma. Their clinical course was characterized by high fever, odynophagia, leukopenia, thrombocytopenia and terminal coagulopathy. Liver enzymes showed hepatocellular disease. Hepatomegaly with scattered hemorrhagic areas was generally present postmortem. In renal transplant patients, Pien and Smith et al. [87] documented a fourfold or greater seroconversion in nine of 17 patients for HSV and in six of 17 for varicella/ zoster. Seroconversion generally occurred two months after transplant. Culture of blood given these patients as transfusions or blood from the kidney donors in all cases failed to isolate the virus. In none of the five patients who had no HSV antibodies before transplantation did a fourfold or greater increase in HSV antibody titers occur; in none of 12 with a titer of > 1:4 did this same rise occur. This suggests either activation of latent virus in the recipient or greater ease of reinfection after the transplantation. Infection in these patients was mild, resembling an upper respiratory tract infection, and was not reported to include hepatic disease. Severe infection has been reported. Montgomerie et al. [88] described four patients who died of dis-

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seminated HSV infection after receiving a renal transplant. These infections involved face, mouth, esophagus, ileum and anogenital areas. These investigators believed this infection was an important contributing factor in the death of three other patients. Ware et al. [49] described 11 patients in whom clinical HSV infections developed after they received a renal transplant. Six had no liver disease, one had acute hepatitis and two had chronic hepatitis. The histologic pattern in this latter group ranged from normal to postnecrotic cirrhosis or chronic active hepatitis. They commented that the clinical and pathologic features of liver disease in this group are indistinguishable from those presumed to be due to hepatitis B or CMV. Anuras and Summers [89] recently described a 31 year old renal transplant recipient in whom disseminated HSV infection developed with fulminant hepatic failure and disseminated intravascular coagulopathy. Postmortem liver cultures were positive for herpes simplex. Therapy for HSV infections has included Idoxuridine, Ara-C, and Ara-A, and in some cases has appeared encouraging. However, controlled studies are lacking [90-931. Furthermore, none of these cases involved hepatitis. Chronic Active Hepatitis. In the renal transplant recipients, the frequency of hepatic dysfunction progressing to chronic hepatitis has been reported to be between 6 and 16 per cent [ 18,49,94-961. The majority of the patients were asymptomatic or had minimal symptoms of liver disease. These included mild malaise, anorexia, nausea or right upper quadrant pain. These patients exhibited only slight elevation of the serum bilirubin level (usually

Liver disease in renal transplant recipients.

REVIEW Liver Disease in Renal Transplant Recipients JOSEPH SOPKO, M.D. SINN ANURAS, M.D. lowa City, lowa From the Department of Medicine, Univers...
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