In August 2005 a 43-year old woman with known HIV infection since 1998 presented in the emergency department with post-prandial abdominal pain and important weight loss (10 kg) over 4 months. HIV infection was treated since 2000 with a HAART including didanosine, lamivudine and abacavir. At admission her absolute CD4 count was 279/mm3 and HIV viremia 270,000 copies/ml. Diffuse lymphoadenopathy, splenomegaly and ascites were observed associated with biochemical abnormalities of the liver parameters: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 1.5 times upper normal range, alkaline phosphatase (AP) twice and gamma-glutamyltransferase (gammaGT) four times above normal values. There was neither alcohol intake nor toxic exposure; screening was negative for viral hepatitis (HAV, HBV, HDV, HCV and HEV), CMV and EBV, autoimmune hepatitis (antinuclear antibodies, antiactin antibodies and total serum immunoglobulins), Wilson's disease, hemochromatosis and schistosomiasis. A thoraco-abdominal CT scan showed mediastinal and axillar lymphadenopathies, pulmonary nodules and a heterogeneous liver parenchyma with signs of portal hypertension (esophageal varices, ascites and splenomegaly). A transjugular liver biopsy revealed a slightly abnormal portal pressure gradient (8 mmHg wedge gradient) and the histology described normal parenchymal architecture with a minimal portal fibrosis and sinusoidal infiltration of mainly T lymphocytes (CD3+). A lymphoproliferative disease was ruled out by flow cytometry of peripheral blood lymphocytes, intranodal lymphocytes (axillar lymphnode biopsy) and of liver infiltrating lymphocytes. At this point our hypothesis pointed towards a miliary tuberculosis with lung and peritoneal involvement. In the ascites fluid the polymorphonuclear count was low (PMN, <250 cells/mm3) as also the albumin (10 gr/l) and protein level (9 gr/l) with a serum-to-ascites albumin gradient (SAAG) of 2.6 pointing towards portal hypertension. However, the cultures of the ascites fluid tested positive for M. tuberculosis and treatment was started with rifampin, isoniazid (INH) and ethambutol for six months and thereafter bitherapy with INH and rifampin (based on the antibiogram) for additional seven months. An upper gastrointestinal endoscopy evidenced grade I esophageal varices. For the viral breakthrough of HIV, HAART was changed to tenofovir, efavirenz, atazanavir and ritonavir. The patient was dismissed from the hospital but presented seven, eight, ten and 12 months later severe esophageal variceal bleedings treated with endoscopic band ligation and slerotherapy and beta-blockers (propanolol).
In September 2006 she was admitted again for bilateral leg swelling and important ascites with very low proteins (7 gr/l, serum albumin 30 gr/l, serum-to-ascites albumin gradient SAAG of 2.3). Liver function tests were still abnormal: AST and ALT 1.5 ULN, AP 2x ULN, gammaGT 4x ULN and diminisched Factor V (50%). An abdominal CT scan and MRI showed large volume ascites, splenomegaly and portal-systemic collaterals. The portal vein was patent. A second transjugular liver biopsy revealed again minimal portal fibrosis without significant inflammation. On the reticulin stain a typical nodular rearrangement of the parenchyma with atrophic periportal and regenerative centrolobular plates was compatible with NRH (Figure 1). In addition, fibrous material was occluding portal veins in several portal tracts pointing towards HIV-associated obliterative portopathy.
Hence, in the context of HIV infection, we suspected a hypercoagulable state with micro-thrombosis in the distal portal veins causing NRH. A thrombophilia work-up (lupus anticoagulant, anticardiolipin and anti-beta2-glycoprotein I antibodies, factor II G20210A mutation, factor V Leiden mutation, anti-thrombin, protein C and protein S) showed low level of free protein S antigen (37% normal > 55%). An anticoagulant treatment with vitamin K antagonists (VKA, acenocoumarol) aiming at an INR of 2.0-3.0 was introduced. However, the anticoagulant treatment with VKA was difficult to regulate with highly variable INR, which was repeatedly infra-therapeutic. In November 2006 she presented another variceal bleeding (with an INR at 1.7) controlled by band ligation, ascites and progressive cachexia (BMI 15.6). HIV infection was again uncontrolled and treatment was changed to tenofovir, emtricitabin, lopinavir and ritonavir. Thus, in February 2007 the patient was listed for LT with a MELD score of 14. To bridge until LT a TIPS was placed. Four weeks after the TIPS placement, the anticoagulant treatment with VKA was still extremely difficult to manage with unsatisfactory INR levels. Low platelets counts, factor V level, and fibrinogen (2.1 g/l) together with high D-dimers were suggestive of a persistent consumption coagulopathy and an ongoing thrombotic process. For these reasons, anticoagulant treatment was switched to LMWH in March 2007 for the next two months. With this treatment, the factor V levels increased, D-dimers normalized and fibrinogen increased (to 6.5 g/l); this was all highly suggestive of efficient anticoagulant treatment (resumed in Figure 2). In May 2007 anticoagulant treatment was switched back to VKA and INR could be maintained between 2 and 3. In the following months ascites and lower leg edema disappeared, the nutrition state improved considerably, and finally the patient was removed from the LT waiting list. While writing this report the patient was well with a BMI of 21.