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CLINICAL SCIENCE: CONCISE COMMUNICATION

Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients

Mallet, Vincenta,b,e,*; Blanchard, Pierreb,*; Verkarre, Virginiea,c; Vallet-Pichard, Anaïsa,b,e; Fontaine, Hélèneb,e; Lascoux-Combe, Carolined; Pol, Stanislasa,b,e

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doi: 10.1097/QAD.0b013e3280119e47
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Abstract

Introduction

In the era of HAART, liver disorders are responsible for an important and increasing number of deaths among HIV-infected patients [1,2]. Main causes of chronic liver disease in HIV-infected patients are infection by hepatitis B and C viruses, alcohol consumption, insulin resistance syndrome [3] and drug-induced toxicity. Sometimes, the etiology of liver damage remains unknown and is designated as cryptogenic. This entity seems to accounts in 0.5% of HIV-positive patients, and may lead, in some cases, to the complications of portal hypertension [4]. HIV-associated cryptogenic liver disease has, to date, never been fully described: the mechanisms involved, its clinical importance and prognosis are for the moment unknown.

Nodular regenerative hyperplasia (NRH) of the liver is characterized by the presence of diffuse rather small regenerative nodules in the absence of significant fibrosis. Its prevalence is estimated between 0.72 and 2.6% on autopsy series [5,6]. The pathogenesis of NRH is not completely understood, but the current theories favour a primary vasculopathy with alterations in blood flow [6–8]. NRH has been associated with systemic diseases, including, vascular, cardiac, rheumatologic and hematological disorders, as well as certain drugs and toxins [9]. The association of NRH and HIV-infection has been recently described in a patient and was thought to be due to interleukin-2 therapy [10]. We report and describe the clinical and morphological features of eight consecutive HAART-treated HIV-positive patients with cryptogenic liver disease. All had symptomatic intra-hepatic portal hypertension secondary to nodular regenerative hyperplasia.

Methods

Definition of cryptogenic liver disease

The diagnosis of cryptogenic liver disease was considered if one or more of the following signs was present without a common cause of liver disease: (1) persistently (more than 6 months) abnormal liver function tests; (2) clinical, biological or endoscopic signs of portal hypertension; (3) ultrasonographic liver dysmorphia. In all patients, genome amplification of viral B (HBV) and C hepatitis (HCV) were negative with a detection limit of 2000 copies/ml and 50 IU/ml, respectively, excluding overt or occult HBV and/or HCV infection. Hepatitis B core antibodies (HBc) antibodies (IgG) were positive in three of eight patients. There was no past or recent history of excessive alcohol consumption (> 20 g/day),no toxic exposure (vitamin A, copper sulphate, vinyl chloride monomer, thorium sulphate, Spanish toxic oil or arsenic salts), no past or ongoing hormonal therapy or herbal medicine practice. Ferritin and transferrin saturation blood levels were normal, anti-liver auto-antibodies and anti-nuclear antibodies were tested negative, serum alpha-1-antitrypsin, copper and ceruloplasmin levels were normal, which ruled out hemochromatosis, auto-immune hepatitis, alpha-1-antitrypsin deficiency and Wilson's disease, respectively.

Pathology

All patients underwent liver biopsy, either transvenous (n = 1) or transcutaneous (n = 7), after they gave consent. Liver sections were stained with haematoxylin-eosin, Sirius Red, reticulin argentation (Gomeri's method) and Perls coloration. All sections were evaluated by the same pathologist (see Table 3 below). Nodular regenerative hyperplasia was defined as a nodular architecture without extensive fibrosis or as the association of thickened and atrophic liver cell plates [6]. Sinusoidal dilatation was defined as sinusoidal spaces more than one hepatocyte plate in width without any other histological abnormality [11].

Results

Incidence/prevalence

From January 2003 to June 2006, eight consecutive HIV-infected patients (seven Caucasian and one African) were referred for cryptogenic liver disease to the liver unit of Necker University Hospital (Paris, France). During the same period, 178 HIV-infected patients were admitted to the same unit for the treatment or the evaluation of chronic liver disease and 97 underwent liver biopsy. The median delay between the onset of the first liver-related symptoms and diagnosis was 21 months (range, 1–70 months).

Clinical presentation

Clinical characteristics of the patients are presented in Table 1. Median age was 39 years (range, 33–59 years). There were four female and four male individuals. Median body mass index was 20.0 kg/m2 (range, 16.5–21 kg/m2). With the exception of HIV infection and the associated liver disease, none of these patients had significant co-morbidity, especially considering cardiac or renal pathology. They did not take any other hepatotoxic medication apart from antiretroviral drugs.

T1-8
Table 1:
Characteristics of patients at the time of diagnosis of nodular regenerative hyperplasia.

The initial mode of presentation was anicteric cholestasis with mild cytolysis in five patients, occult portal hypertensive hemorrhage in two, and pancytopenia secondary to splenic sequestration in one. All patients had evidence of portal hypertension at clinical, biological, endoscopic or ultrasound examination. Ascites was present in three patients. Upper digestive endoscopy showed portal hypertensive gastropathy in all patients, grade II esophageal varices in six patients and grade III varices in two. All had mild thrombopenia with a median platelet count of 121 000 per mm3 (range, 71 000–149 000 per mm3). Hepatic ultrasonographic dysmorphy, defined as atrophy/hypertrophy of at least two segments of the liver, was present in six cases. Other ultrasonographic findings included splenomegaly (n = 7) and collateral venous derivation (n = 4).

Characteristics of HIV infection

No patients had had opportunistic infection (Table 2). The median nadir of CD4 cell count was 205 cells/μl (mean, 243 cells/μl; range, 86–331 cells/μl). At time of diagnosis, all patients were treated by HAART with an efficient immune restoration. HIV viral load was below 50 copies/ml in five patients and below 4.85 log copies/ml in the others (patients 2, 6 and 7). The median CD4 cell count was 242 cells/μl (mean, 294 cells/μl; range, 142–650 cells/μl). Among the several lines of antiretroviral drugs, they received before NRH diagnosis, all patients had taken didanosine.

T2-8
Table 2:
Characteristics of HIV infection and treatments at the time of diagnosis of nodular regenerative hyperplasia (NRH).

Pathology findings

The median length of liver biopsy was 20 mm (mean, 19 mm; range, 12–27 mm), and more than seven portal tracts were studied in each biopsy (mean, 13; range, 7–23). A clear nodular architecture was seen in seven patients, whereas in the last one, NRH was suspected on the presence of sinusoidal dilatation in a clinical context of portal hypertension (patient 3) (Fig. 1 and Table 3). Portal and biliary tracts were normal in each specimen. There was no iron overload after staining with Perls coloration. Macrovacuolar steatosis was seen in two patients (patients 1 and 3), in 5 and 20% of liver cells, in the absence of metabolic syndrome.

F1-8
Fig. 1:
(a) Nodular regenerative hyperplasia of the liver. Nodular architecture in the absence of significant fibrosis. Reticulin argentation (Gomeri's method); original magnification × 5; patient number 1. CV, central vein. (b) Nodular regenerative hyperplasia of the liver. Thickened (arrow 1) and compressed liver cell plates (arrow 3) with dilatation of the sinusoidal space (arrow 2). Reticulin argentation (Gomeri's method); original magnification × 10; patient number 1.
T3-8
Table 3:
Pathological findings in eight HIV-infected patients with nodular regenerative hyperplasia.

Perisinusoidal fibrosis was found in three patients. Rare portal fibrosis was present in only one specimen, but without septum. There was a mild sinusoidal lymphocyte infiltrate in three biopsies.

Management and outcome

During follow up, four patients experienced variceal hemorrhage, two patients had portal vein thrombosis and two patients had ascites. Treatment was symptomatic, following the same protocol as in cirrhosis. A transjugular intrahepatic portosystemic stent shunt (TIPSS) failed to control portal pressure in patient 4. To date, all patients are alive, and three are waiting for liver transplantation.

Discussion

The diagnosis of nodular regenerative hyperplasia (NRH) is frequently missed. This may be due to a prolonged asymptomatic subclinical period and the difficulties associated with confirmation of the diagnosis, even on liver biopsy. NRH is frequently a satellite of systemic disease including chronic cardiac failure [12], myeloproliferative disorders [13], auto-immune diseases (e.g. rheumatoid arthritis or lupus erythematosus) [14], infections (tuberculosis, endocarditis), drug-toxicity [15], hypercoagulable states [16,17] and malignancies [13]. We report a series of patients with NRH in whom HIV infection and HAART were the only identified etiologic factors.

The diagnosis of NRH was made on the basis of micronodulation with an alternation of thickened and compressed liver cells in seven patients and suspected with the association of sinusoidal dilatation and clinical signs of portal hypertension. Other pathological findings included perisinudoidal fibrosis and sinusoidal dilatation. All of these findings have been previously described along with NRH [18–20] and are consistent with the vascular origin of NRH. In fact, NRH is thought to result from the occlusion of terminal branches of the hepatic arterioles and portal veinules, consisting in a non-specific tissue adaptation to heterogeneous distribution of blood flow [6].

In HIV-infected patients, NRH could result from different causes. First, opportunistic infection could be involved, as in cases of bacillary angiomatosis. This hypothesis seems unlikely, because none of our patients had a past history of opportunistic infection. Antiretroviral therapy is a second factor that could explain NRH [21]. In a recent review, severe drug hepatotoxicity was reported in 2 to 18% of HAART-treated patients [21]. Among all antiretroviral agents used, it is noteworthy that didanosine was the sole molecule received by all of our patients. Some drugs are known to induce vascular disease (e.g. estrogens, azathioprine, etc.) but to the best of our knowledge, neither nucleoside inhibitors of reverse transcriptase nor protease inhibitors have, to date, been associated with vascular liver disease or to a clear prothrombotic state. In a case–control analysis dealing with cryptogenetic liver disease in HIV-infected patients, didanosine intake was statistically associated with the occurrence of cryptogenetic liver disease and the duration of didanosine exposure was a significant associated variable [4]. Third, HIV itself could explain NRH. HIV is thought to trigger HIV-associated pulmonary hypertension by direct endothelial toxicity [22]. A similar mechanism could be thought of in the liver. A prothrombotic state is a fourth possible cause. HIV is associated with an increased risk of thrombosis [23], and thus could favor, as previously described, NRH and non-cirrhotic portal hypertension [16,17]. If we combine all these non-exclusive mechanisms, we speculate that a prothrombotic state enhanced by both HIV infection and didanosine toxicity may result in intrahepatic thrombosis leading to NRH.

Without a clearly identified etiology for HIV-associated NRH, management remains symptomatic [15]. NRH classically leads to portal hypertension but not to hepatocellular dysfunction [6]. Nevertheless, cases of hepatic encephalopathy have been described after portal shunting [24], suggesting the presence of liver failure. In our experience, shunting procedure, either using intra-hepatic shunt or surgical procedure, can lead to hepatic encephalopathy in patients with NRH following kidney transplantation, even in absence of liver failure (unpublished data). In this study, four out of eight patients had a diminished prothrombin and clotting factor V serum levels, suggesting mild liver failure. Liver transplantation remains an option if NRH is responsible for refractory ascites, spontaneous infections of ascites or threatening esophageal varices despite repeated endoscopic ligature procedure. A few cases of liver transplantation for NRH have been reported with good results [25,26], but never in HIV-associated NRH. If the HAART regimen includes known hepatotoxic drugs, such as didanosine or stavudine, replacement of these antiretroviral drugs by others should be discussed.

To sum up, we have described a case series of eight consecutive cases of HIV-associated NRH corresponding to a prevalence of approximately 8% over a period of 3 years in our ward; this prevalence is probably underestimated. NRH may result in dramatic complications, the first one being bleeding from esophageal varices. When facing an HIV-infected patient presenting abnormal hepatic tests (cholestasis, thrombopenia) or clinical signs of liver disease, especially in a didanosine-exposed patients, the usual causes of liver disease should first be ruled out, but the diagnosis of NRH should be discussed, in order to detect portal hypertension and to prevent the risk of variceal hemorrhage. Many questions remain unanswered, such as the cause of NRH in HIV-infected patients, its prevalence and management, the potential role of prothrombotic states and the advantage of withdrawing hepatotoxic antiretroviral drugs. Among potential causes of NRH, HAART toxicity should be carefully examined.

Acknowledgement

We are grateful to Dr. Jean-Paul Viard for reviewing the manuscript.

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Keywords:

HIV; liver; portal hypertension; antiviral therapy

© 2007 Lippincott Williams & Wilkins, Inc.