For portal hypertension, the patient was treated with propranolol with appropriate dosage increases on an interval basis and also given iron for anemia. Since discharge he has been well and has not had hematochezia, melena, or hematemesis. He was restarted on HAART regimen of tenofovir, emtricitabine, darunavir/ritonavir, and raltegravir with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis 2 months after discharge. Four subsequent endoscopies with variceal banding were performed during an 11-month period. Interval decreases in both the number and size of esophageal varices were evident, with the most recent endoscopy demonstrating no more than grade 1 to 2 esophageal varices, although portal gastropathy was still visible. At last follow-up the platelet count was 91,000/mm3, international normalized ratio 1.4, albumin 3.5 g/dL, total bilirubin 1.8 mg/dL, direct bilirubin 0.4 mg/dL, and transaminases normal. He continues to be followed closely for any elevation of liver transaminases, reduced hepatic function, or elevated α-fetoprotein as well as regular imaging of his liver to monitor for lesions suspicious for hepatocellular carcinoma or alterations in hepatic vascular flow.
Acute hepatitis, giant cell hepatitis, infection with hepatotropic viruses (hepatitis B virus, hepatitis C virus), and opportunistic pathogens have been recognized in children with the later stages of HIV infection (5). A chronic and subclinical hepatotoxicity of the nucleoside reverse transcriptase inhibitors didanosine and stavudine and the nonnucleoside reverse transcriptase inhibitor nevirapine has been reported to occur in approximately 2% to 18% of treated patients and is associated with duration of therapy (6). Hepatic dysfunction may range from minimal to liver failure, and interruption of treatment may be necessary (7). HIV-associated malignancy may contribute to liver disease. The HIV virus has been speculated to directly induce a hypercoagulable state through activation of endothelial cells and decreased hepatic production of anticoagulant factors, and induce cryptogenic liver disease such as HPS and NRH (8).
HPS and NRH may share a common mechanistic pathway of compromised intrahepatic portal venous flow (3,4). The histological appearance of HPS includes subintimal fibrosis of small portal venous branches with thickening of the venous walls, and dilatation of sinusoids (megasinusoids) without cirrhosis (1). Identified associations with HPS include spherocytosis, neonatal omphalitis, neonatal umbilical catheterization, extrahepatic portal vein thrombosis, and right kidney agenesis (3). Cytotoxic agents such as azathioprine, thioguanine, chlorambucil, busulphan, vinyl chloride, arsenic, and vitamin A have also been associated with HPS (9). NRH is characterized by multiple small hyperplastic nodules centered around portal tracts compressing adjacent, frequently atrophic liver cells and sinusoids without significant fibrosis (4). NRH may be associated with infection (HIV, tuberculosis, and HCV), cardiac, rheumatologic, hematological, hypercoagulable states, drugs (steroids, oral contraceptives, and HAART), primary biliary cirrhosis, Turner syndrome, and renal and bone marrow/stem cell transplantation (4,8). NRH may occur with partial or complete portal vein obstruction secondary to ischemia and reactive hepatocyte proliferation because of compensatory hepatic arterial blood flow (4).
NRH with associated findings of perisinusoidal or portal fibrosis was recently described in adults on HAART (8,10). Hepatoportal sclerosis was also recently reported in 4 adults presenting with variceal bleeding from portal hypertension on HAART (1). This may be a direct acute hepatotoxic effect of antiretroviral agents or the HIV virus inducing hepatotoxicity, intrahepatic endothelial damage, and a prothrombotic state, and/or alter hepatic fibrinogenesis leading to NRH and/or HPS (1,8,11). The exact mechanism of toxicity from HAART has not been elucidated and is speculated to occur secondary to mitochondrial damage and/or immune reconstitution from hepatic neoantigens created by exposure to reactive drug metabolites (1,6). Although the patient admitted to intermittent noncompliance, basing his exposure on his prescribed HAART regimen (Table 1) indicates prolonged exposure to didanosine, emtricitabine, stavudine, and zidovudine, which are considered to have relatively more hepatotoxic profiles than other medications from his HAART regimen (6). Although it is difficult to determine relative contributions of a particular drug, duration of exposure is a risk factor for the development of hepatotoxicity for some HAART medications (1,6).
Histological obliteration of portal vasculature resulting in HPS and NRH may be due to microthrombosis or macrothrombosis of the right portal vein from inherited protein C or protein S deficiency. Alternatively, coagulation defects leading to thrombosis may be secondary to progressive liver disease and/or represent altered homeostatic coagulatory balance (11). Repeated episodes of pylephlebitis and septic microthrombophlebitis may contribute to the obliteration of portal microvasculature in immunocompromised individuals (12), although this process was not demonstrated here. Liver biopsy in this patient also revealed hepatic steatosis, which is associated with a more rapidly progressing hepatic fibrosis (1). The hypoalbuminemia that subsequently normalized was perhaps a consequence of variceal bleeding. The prolonged modest elevation of total bilirubin may represent hemolysis, decreased hepatic bilirubin clearance as a result of impairment of bilirubin conjugation, or both, which is frequently seen in patients taking HAART and is likely to be of little consequence (6,13).
Management of HPS includes therapy treating portal hypertension and withdrawal of precipitating factors such as hepatotoxic medications. HPS should be considered in the differential diagnosis of patients with variceal bleeding from noncirrhotic portal hypertension, although HPS may be difficult to diagnose even with small needle liver biopsy (1). Secondary prophylaxis following an esophageal variceal bleed includes the use of nonselective β-blockers, endoscopic variceal ligation or sclerotherapy, and shunting via transjugular intrahepatic portosystemic shunts, or surgical shunting (14). The lack of randomized controlled trials evaluating different treatment options for pediatric portal hypertension makes consensus approach difficult. The patient underwent combination therapy with banding and nonselective β-blockers; this strategy has been shown to be superior to banding alone for protection against rebleeding (15). Liver transplantation is feasible in HIV-infected patients with complications of refractory severe portal hypertension and survival was comparable in HIV and non-HIV recipients; however, patients with HIV had significantly higher mortality from infectious complications (16). After liver transplant HAART therapy remains necessary because HIV infection is unresolved; recurrence of NRH has been described after transplant in HIV-infected individuals (10).
In summary, we describe a 15-year-old boy with HIV on HAART who presented with variceal bleeding and was found to have hepatoportal sclerosis with nodular regenerative hyperplasia on liver biopsy. He responded well to endoscopic and medical treatment of portal hypertension. To our knowledge, this is the first report of a child or adolescent with HIV also diagnosed as having hepatoportal sclerosis. There may be an association of prolonged antiretroviral therapy with the development of HPS, although an exact etiology remains elusive. Patients with HIV should be monitored for subtle signs of portal hypertension and HPS should be considered in the differential diagnosis of patients with HIV who develop portal hypertension.
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