Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation

Abstract

The clinicopathologic features of liver allograft dysfunction occurring in 51 symptomatic recipients after more than 5 years' survival (mean 7.1 years) with the same hepatic allograft were compared with those of a similar group of 14 asymptomatic patients (mean survival, 9.9 years) who underwent a nonclinically indicated protocol liver biopsy evaluation. Predictably, patients who had clinically indicated biopsies more frequently showed histopathologic alterations (76% versus 36%, p < 0.002). After detailed clinicopathologic correlation, the changes in the symptomatic patients were attributed primarily to definite or presumed viral hepatitis in 17 of 51 (33%) patients, 11 of whom had recurrent viral disease; seven of 51 (14%) had nonviral recurrent original disease, three (6%) had obstructive cholangiopathy, and 11 (22%) had acute and/or chronic rejection. In 13 of 51 (25%) of the symptomatic patients, the clinical and pathologic abnormalities were minimal. Long-term liver allograft survival in nine of 14 (64%) of the asymptomatic patients was associated with minimally abnormal histologic alterations. Two of the asymptomatic patients had obstructive cholangiopathy; two others has recurrence of the original disease and one has possible viral hepatitis. Viral hepatitis types B and C, alcoholic liver disease, autoimmune hepatitis, granulomatous hepatitis (not otherwise specified), and probably primary biliary cirrhosis and primary sclerosing cholangitis were shown to recur after hepatic transplantation. The histopathologic changes associated with acute and chronic rejection frequently overlapped with other syndromes causing late dysfunction, such as chronic viral or autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis; more than one insult could be identified in 15 cases, which made the differential diagnosis of causes of late liver allograft dysfunction much more difficult than early after hepatic transplantation. It is important to correlate the biopsy findings with the liver injury tests, the results of viral and autoimmune antibody serologic studies, and review of previous biopsies and to be aware of the original disease, recent changes in immunosuppression, and results of therapeutic intervention(s) to identify correctly the causes of liver allograft dysfunction in this patient population.

FIG. 1

Acute cellular rejection in a patient who initially was asymptomatic, then developed liver dysfunction as a result of immunosuppressive weaning. The portal tract (PT, inset) and pericentral vein (CV) inflammation and liver injury tests worsened after cyclosporin A steroid withdrawal and improved after restarting treatment.

FIG. 2

Chronic viral hepatitis type C often appeared histopathologically similar to that seen in nontransplanted livers, as shown here, with lymphoid nodules in the portal triads, piecemeal necrosis, sinusoidal lymphocytosis, mild steatosis, and spotty lobular necrosis. In other cases of hepatitis C virus, the inflammation was mild and neutrophilic predominant, but marked cholangiolar proliferation, more typical of a “cholestatic hepatitis,” was seen.

FIG. 3

Hepatic arteriolar thickening and hyalinization with intact bile ducts was seen in patients with minimal other changes and was attributed to hypertension, diabetes, or chronic cyclosporin injury, similar to the lesions seen in the kidney.

FIG. 4

(a) Mild intralobular regenerative activity characterized by thickening of the plates and even focal nodule formation was a frequent but subtle finding in many of the long-term survivors, even in those without symptoms or other pathologic changes. (b) A reticulin stain shows the subtle areas of intralobular regenerative change with thickening of the plates.

FIG. 5

Recurrent alcohol abuse was most frequently (in three of four cases) associated with centrilobular mixed steatosis with “foamy” degeneration of hepatocytes (inset), lobular neutrophil clusters, perivenular and subsinusoidal fibrosis, and Kupffer’s cell iron deposition. One other patient who admitted to alcoholic relapse showed moderate reticuloendothelial iron deposition, portal and sinusoidal fibrosis, but no steatosis. As always, other causes of steatohepatitis should be excluded.

FIG. 6

This periductal granuloma with minimal duct damage was seen in a biopsy obtained 6 years after transplantation in one of 16 patients whose original disease was primary biliary cirrhosis and in no other patients, regardless of the original disease.

FIG. 7

Possible recurrent sclerosing cholangitis (with a component of rejection?) was suspected in this failed allograft (1.100 g) removed 7 years after transplantation. (a) There was a well-developed biliary-type cirrhosis with decreased bile ducts and deposition of copper-associated protein at the edge of the regenerative nodules (inset), but no classic “fibro-obliterative” duct lesions. (b) Sections through the liver hilum showed chronic inflammation of large bile ducts and mural fibrosis but no obliterative arteriopathy.