Chronic Hepatitis C of 28 Years' Duration Characterized by Early Development of Stage 2 (of 4) Fibrosis but No Significant Progression over the Subsequent 18 Years

CASE REPORT

A 29-year-old attorney was referred to one of the authors (P.D.B.) at Sinai Medical Center (New York) on July 1, 1982 with jaundice, malaise, nausea, vomiting, and diffuse ecchymoses. The ecchymoses developed several days earlier after the patient slid into second base during a softball game between New York law firms. The other symptoms evolved over the subsequent 24 hours. Although his symptoms were thought by his referring physician to reflect an acute hepatitis, the absence of bilirubin from the urine during his initial outpatient evaluation pointed toward a hemolytic rather than a hepatic cause for the jaundice. The presence of multiple schistocytes and virtual absence of platelets in his peripheral blood smear suggested a diagnosis of thrombotic thrombocytopenic purpura (TTP), for which he was immediately hospitalized. His admission physical examination was notable only for jaundice and the extensive echymoses. Admission laboratory data included: Hgb 7.1 g/dL, Hct 19.6%, reticulocytes 8.6%, WBC 10,100/μL, and platelets 10,000/μL. In addition to schistocytes, his peripheral blood smear showed nucleated red blood cells and a marked shift to the left in the neutrophilic series, with 6% metamyelocytes and myelocytes. Total and direct bilirubin were 10.5 and 1.6 mg/dL, respectively. Serum aspartate and alanine aminotransferases (AST and ALT) and alkaline phosphatase, at 52, 38, and 72 IU/L, respectively, were all within the normal range. A bone marrow aspirate revealed marked megakaryocytic hyperplasia, and moderate erythroid hyperplasia with normal erythroid maturation. Direct and indirect Coombs' tests and anti-platelet antibodies were negative.

Although he was neurologically intact on admission, a surgical consultation was obtained and contingency plans were made for an emergency splenectomy should his condition worsen. Early on the morning of July 3, 1982 the patient was found to be aphasic and then to have evidence of progressive cortical dysfunction. Within hours he underwent emergent open splenectomy. The enlarged, 495 g spleen was congested but showed a generally well-preserved architecture with increased red pulp. Typical of TTP, fibrin thrombi were present in middle- and large-sized vessels. An intraoperative wedge liver biopsy was also obtained, revealing only minimal steatosis, centrilobular congestion, and granulocytic infiltration of the sinusoids.

In the face of profound anemia and thrombocytopenia he was supported with massive platelet and red blood cell transfusions, which began preoperatively and ultimately amounted to more than 100 units of blood products, each from a single donor. He was also treated with exchange plasmapheresis daily for 10 days, low molecular weight dextran (Dextran 70) for 2 weeks, and corticosteroids, the latter as 1 g Solucortef intravenously immediately postoperatively, followed 48 hours later by oral prednisone at an initial dose of 80 mg daily.

His complicated postoperative course, including transient elevations in AST, ALT, and bilirubin during the first postoperative week, began to improve steadily by the second week. Remarkably, the patient recovered from this acute episode, his TTP went into complete remission, and he was discharged home on August 12, 6 weeks after admission. At discharge, his laboratory studies were significant for normal hemoglobin, white blood cell and platelet counts, and an absence of schistocytes in his peripheral smear. Hepatic biochemical tests were normal except for mild unconjugated hyperbilirubinemia, which persisted after the resolution of any evidence of hemolysis, and was subsequently attributed to Gilbert's syndrome. His medications on discharge included a gradual prednisone taper.

The patient was readmitted from August 28 to October 7 with an acute hepatitis manifested by a peak AST of 3575 IU/L and ALT of 2750 IU/L. Serologies for hepatitis A and B were negative, and he was considered to have acute, post-transfusion non A-non B hepatitis. A recurrence of a postoperative sub-phrenic abscess was drained surgically. His transaminases declined slowly but steadily until discharge. The prednisone taper was continued, and was completed by late November 1982 after nearly 5 months of steroids.

At subsequent follow-up visits, intermittent elevations in AST and ALT were noted. The diagnosis of non-A non-B hepatitis was confirmed to be due to hepatitis C virus (HCV) in 1989, shortly after HCV testing became available, and he was ultimately found to have genotype 1a disease. The route of transmission was presumed to be the blood product transfusions he received while hospitalized. Over the following decade he was treated for HCV three times without achieving a sustained virologic response. He first received 6 months of interferon α-2B monotherapy at a dose of 3 million units three times weekly in 1992, to which he responded completely while on therapy but relapsed after discontinuation of treatment. When ribavirin became available, he was retreated with a combination ribavirin and interferon α-2B in 2000. He again achieved viral clearance by 12 weeks, but relapsed 3 months after therapy was completed.

Finally, with the availability of pegylated interferon, he was again retreated with a combination of ribavirin 1000 mg in divided daily doses and pegylated-interferon α-2B 120 micrograms weekly beginning in the fall of 2002. He once again achieved a negative viral load by 12 weeks, but the planned 48 weeks of treatment had to be discontinued at 10 months when he developed severe hypoalbuminemia out of proportion to other, essentially normal, hepatic biochemical tests, and was found to have nephrotic range proteinuria. He underwent a renal biopsy which revealed normal-appearing glomeruli, interstitium, tubules, and vascular structures but effacement of podocyte foot processes on electron microscopy. He was diagnosed with a rare complication of interferon therapy: nephrotic syndrome of the minimal change type. With discontinuation of interferon-based HCV treatment, his proteinuria resolved but the HCV quickly relapsed.

Currently, 28 years after his presumed blood-product associated infection with HCV, the patient is a busy practicing attorney who remains entirely asymptomatic, without significant sequelae of his HCV disease. His most recent blood test results, in January 2010, included an HCV viral load of 997,727 IU/mL, mildly elevated aminotransferases (AST 62 IU/L, ALT 105 IU/L), but normal albumin, platelets, and coagulation parameters. He has no evidence of portal hypertension on physical exam or imaging He has no history of significant alcohol use throughout this period, and has tested negative for human immunodeficiency virus (HIV) or hepatitis B virus (HBV) co-infection.

Liver Disease Progression

The patient has had an unusual course of HCV disease progression. He has undergone six liver biopsies in the 28 years since he acquired the disease, each done for clinical reasons but offering a rare glimpse at the natural history of his disease with serial histological examinations over time.

Other than the intraoperative biopsy in 1982 described above, which had no features suggestive of hepatitis, the first biopsy obtained specifically for evaluation of chronic hepatitis was in September 1990, 7œ years after acquiring HCV. It revealed chronic hepatitis with mild piecemeal necrosis and occasional lymphoid aggregates consistent with chronic HCV. In addition, he already had mild portal fibrosis and rare thin fibrous septa linking portal tracts, compatible with stage 2 of 4 fibrosis in the Scheuer[1] (Batts-Ludwig) staging system. No significant steatosis or other disease processes were identified. A second biopsy in February 1992 reportedly showed chronic hepatitis with moderate piecemeal necrosis, moderate lobular activity, portal fibrosis, and fibrous septum formation consistent with HCV. The extent of fibrosis was not scored by the pathologist, but the description is compatible with stage 2. We were unable to retrieve the slides of these two biopsies.

Pathologic Findings

The last four biopsies, spanning 12 years from 1996 to 2008, were available for additional review. The biopsy from 1996 (Fig. [1]) showed mild chronic hepatitis in the form of portal tract infiltrates of lymphocytes and scattered plasma cells, with focal interface hepatitis (necroinflammatory grade 2 of 4). There was also mild periportal fibrosis (stage 2). Biopsies from 1999 (Fig. [2]), 2001 (Fig. [3]), and 2008 (Fig. [4]) showed similar features of mild chronic HCV with mild fibrosis (grade 2, stage 2). The most recent biopsy (from 2008) showed a slight reduction in necroinflammatory activity, including loss of interface hepatitis (grade 1), but persistent periportal scars (stage 2) and a few periportal regions of regenerative hyperplasia and early nodularity. However, neither significant bridging fibrosis nor cirrhosis was demonstrated and the architecture remained stage 2 of 4.

Figure 1 (A) Chronic hepatitis C—1996 liver biopsy. Chronic hepatitis with portal and periportal lymphoplasmacytic inflammation (arrow) is present. (B) Mild activity (grade 2) is evident in the form of focal periportal interface hepatitis (arrow). Periportal (stage 2) fibrosis was also apparent. (A,B: Hematoxylin and eosin stain.) Figure 2 (A) Chronic hepatitis C—1999 liver biopsy. Portal tracts show numerous lymphoid aggregates (LA), a characteristic feature of HCV infection, as well as expansion by lymphocytes and plasma cells and periportal fibrosis. (B) Mild periportal foci of interface hepatitis are present (arrows) and associated with stellate periportal fibrosis (grade 2, stage 2). (A,B: Hematoxylin and eosin stain.) Figure 3 (A) Chronic hepatitis C—2001 liver biopsy. There is no significant architectural change since the previous biopsy and portal tracts continue to show mild chronic inflammation and interface hepatitis. (B) Mild chronic portal and periportal inflammation is present (grade 2). (C) Periportal fibrosis (stage 2) is seen on trichrome stain. (A,B: Hematoxylin and eosin stain; C: Masson trichrome stain.) Figure 4 Chronic hepatitis C—2008 liver biopsy. Chronic inflammation is confined within portal tracts (right) and the architectural relationships of portal tracts to central veins (left) are intact. (Hematoxylin and eosin stain.) Inset: While slight structural abnormalities, particularly stellate periportal scars, are present, there is no significant bridging fibrosis or cirrhosis. (Reticulin stain.)

Therefore, in the six biopsies performed over a period of 18 years he has stable stage 2 fibrosis and some reduction in necroinflammatory score over time. Despite the development of stage 2 disease in less than 8 years from the time of infection, his disease has not significantly progressed on biopsy over the subsequent two decades, in the face of persistent chronic HCV infection and histological necroinflammation.

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