Human Immunodeficiency Virus Infection of the Liver

Basic Liver Reactivity Pattern to Human Immunodeficiency Virus Infection

Although HIV does not cause distinctive microscopic lesions in the liver, a constellation of histologic findings representing reactivity of the liver to the presence of virus has been reported in biopsy and necropsy studies by several authors ( Fig. 17.1 ). This spectrum is seen in patients with HIV/AIDS who have not undergone any type of treatment and who do not have hepatic or systemic infections, and therefore solely represents a response of the liver to the presence of HIV within the organ. Patients may have increased biochemical liver tests. Although common, these HIV-dependent hepatic manifestations are rarely fatal and patients do not usually develop liver failure.

Microscopically, the histologic findings of HIV-dependent liver reactivity include:

• Diffuse hyperplasia and hypertrophy of Kupffer cells, showing increased cytoplasmic and nuclear volume. The PAS stain shows PAS-positive granules indicating increased phagocytic activity.

• Foci of narrowing of sinusoidal lumen, which correspond to widening of the Disse by increased reticulin fibers. Frequently, these areas alternate with areas of sinusoidal dilation.

• Small foci of mononuclear lobular inflammatory infiltrate.

• Occasionally, non-necrotizing microgranulomas, which are negative for microorganisms.

• Variable degree of hepatocellular steatosis.

• Increase in lipofuscin pigment in hepatocytes.

• Multifocal areas of hemosiderosis in Kupffer cells, sinusoidal endothelial cells, and portal macrophages.

• Portal tracts with edema and mononuclear inflammatory infiltrate.

• Presence of antigens (p24) and viral particles (HIV) in Kupffer cells and endothelial cells.

• Large cell changes in approximately 50% of the cases.

• Bile duct injury (necrosis and inflammation) in the absence of other possible causes.

We have observed the following ultrastructural alterations in these biopsies:

• Increased volume of Kupffer cells with massive nuclei and abundant cytoplasm showing signs of intense phagocytic activity with numerous phagolysosomes.

• Increased lipofuscin pigment and autophagic vacuoles in hepatocytes distributed irregularly within the lobule.

• Increased volume of stellate cells (Ito cells) with ramified cytoplasmic processes, numerous fat vacuoles, and increased granular endoplasmic reticulum.

• Increased perisinusoidal space (or Disse space) containing amorphous electrodense nonfibrillar material, deposited among thin fibers laid down haphazardly in several directions and small collections of collagen fibers.

Visceral Leishmaniasis

Visceral leishmaniasis occurring against a background of AIDS affects predominantly men who have sex with men (MSM) and intravenous drug users, as a reactivation of latent infection. The clinical presentation is not characteristic of visceral leishmaniasis described outside the setting of AIDS; thus, isolated symptoms occur, such as fever and lymphadenopathy, which are not always accompanied by hepatosplenomegaly and pancytopenia. Disseminated infection, affecting unusual sites (eg, the skin); concomitant opportunistic infections; lower therapy response; development of drug resistance and high rates of recurrence after treatment are common pictures in the leishmaniasis in AIDS patients. Serum antibodies against Leishmania are often negative (more than 40%).

The histopathologic diagnosis is suspected when there is marked hypertrophy and hyperplasia of Kupffer cells. The organisms may be seen on an H&E stain as tiny basophilic particulate matter within Kupffer cells ( Fig. 17.2 and eSlide 18.5 ) and are better visualized on a Giemsa stain, which demonstrates a “dot and dash” pattern representing the nucleus and kinetoplast, respectively. Organisms are also seen within portal macrophages. Intralobular and portal mononuclear inflammatory infiltrates, with a predominance of plasma cells, are seen. There is no damage to the limiting plate, and significant hepatocyte necrosis is not present. There may be macrovesicular or microvesicular steatosis distributed randomly within the lobule.

When H&E and Giemsa stains do not suffice in delineating the morphology of the organisms, immunohistochemistry (see Fig. 17.2 ) and polymerase chain reaction may be necessary to establish the diagnosis. Other microorganisms that infect Kupffer cells and produce a similar histologic picture are Histoplasma (see eSlide 19.5 ), which can be identified by silver stains such as Grocott methenamine silver or by immunohistochemistry, and Trypanosoma in acute or reactivated Chagas disease, which can be identified by immunohistochemistry or molecular methods.

Hemophagocytic Lymphohistiocytosis

HIV can precipitate hemophagocytic lymphohistiocytosis (HLH), both in the presence and absence of concurrent infections and malignancy. The onset of HLH in patients with HIV in the absence of an infection or malignancy suggests an independent role of the virus in at least some cases. Other studies have reported HLH as the initial presentation in patients infected by the HIV virus, and in others, it has been associated with immune reconstitution.

A rare and frequently fatal disease in spite of treatment, HLH is caused by the dysregulation of natural killer T-cell function, which results in uncontrolled and ineffective immune activation. This in turn leads to activation and proliferation of lymphocytes and histiocytes with uncontrolled hemophagocytosis and overproduction of cytokines, causing cell damage and multiorgan dysfunction and failure. The process affects the entire reticuloendothelial system, causing pancytopenia, hepatosplenomegaly, and lymphadenopathy.

HLH is considered to be primary when there is no obvious underlying cause. Most often, the syndrome occurs secondary to underlying infections or malignancy; known associations include viruses (herpes simplex virus, varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus [EBV], human herpesvirus 6, human herpesvirus 8 [HHV-8], HIV, adenovirus, influenza virus, hepatotropic virus); bacteria (mycobacterium, spirochetes); fungi; protozoa; and malignant diseases. The primary form is often familial and is thought to have a genetic basis. However, an underlying genetic propensity to immune dysfunction probably underlies all forms of HLH.

The diagnosis of HLH is based on clinical and laboratory evidence and on histopathologic findings. The main symptoms are fever and splenomegaly; jaundice, hepatomegaly, lymphadenopathy, rash, and neurologic alterations are also frequent. The main laboratory finding is cytopenia, which affects more than two cell lines and is characterized by hemoglobin 9 g/dL or less, platelets less than 100,000/μL, and neutrophils less than 1000 cells/μL. Also variably observed are hypertriglyceridemia and/or hypofibrinogenemia, hyperferritinemia, low or absent natural killer cell cytotoxicity, and increase in soluble CD25.

Histologic diagnosis is made on tissue biopsy by the finding of hemophagocytosis in activated macrophages, which contain leukocytes, erythrocytes, and platelets. Hemophagocytosis can be observed in several organs and tissues including the bone marrow, lymph nodes, liver, and spleen. In the liver, there is marked Kupffer cell hypertrophy and hyperplasia, which contain erythrocytes and lymphocytes (see Fig. 17.2 ) (see eSlide 1.12 ). Variable degrees of cholestasis may be seen. Hemosiderin is present to a variable degree in Kupffer cells and hepatocytes. There may be mononuclear inflammatory infiltrate in portal spaces, which does not destroy the limiting plate.

Coinfection With Human Immunodeficiency Virus and Hepatitis C Virus

HCV infection is currently considered one of the most significant opportunistic infections in patients infected with HIV and represents a crucial comorbid factor in this population. Serologic studies have shown that 15% to 30% of patients with HIV are also positive for HCV. Patients coinfected with HIV/HCV have an accelerated course of progression to cirrhosis and terminal liver disease, when compared with patients infected with HCV alone. When comparing the two groups, Allory and associates observed higher METAVIR activity scores in coinfected patients than in those infected with HCV alone. The same study showed that cirrhosis was more frequent in patients with 200 cells/μL or less CD4+ T lymphocytes compared with HIV-negative patients. The role of immune effectors cells in the progression of liver fibrosis in HCV is not well known. However, several studies have observed that low levels of peripheral CD4+ T lymphocytes are associated with faster progression of the liver disease in patients infected with HIV/HCV; the possibility that CD4+ T lymphocytes may have a protective role against progression of fibrosis has therefore been suggested. On the other hand, studies have shown that in spite of a decrease in CD4+ T lymphocytes, including in the intrahepatic compartment, the tissue response with interferon (IFN)-γ is maintained. An increase in the production of inflammatory cytokines of the Th1 pathway has been noted, particularly those with significant fibrogenic role that target not only hepatocytes, but also Kupffer cells and stellate cells.

The histologic picture is similar to that described for chronic hepatitis C infection ( Fig. 17.4 ), although the disease may be more active. Fibrosing cholestatic hepatitis and multinucleated giant cells (syncytial cells) have been described. In addition, other pathologic conditions associated with HIV infection may be superimposed on the chronic hepatitis.

Coinfection With Human Immunodeficiency Virus and Hepatitis B Virus

The prevalence of HBV coinfection in patients infected with HIV is estimated to be 5% to 10%, a much smaller number compared with the 15% to 30% of patients with both HIV and HCV. However, studies have demonstrated higher mortality rates in patients coinfected with HBV, especially those who are hepatitis B surface antibody–positive. When evaluating liver disease-associated mortality in HIV-positive patients, Salmon-Ceron and coworkers demonstrated that HIV/HBV -infected patients accounted for one fifth of all deaths, with 88% of deaths being attributed to decompensated cirrhosis and 15% caused by hepatocellular carcinoma. It is noteworthy that patients with HIV/HBV accounted for 50% of all cases of hepatocellular carcinoma.

The aim of treatment in HIV/HBV coinfection is to suppress viral replication and HBV DNA production, promote seroconversion, normalize transaminases, and reduce or abolish histologic activity. Patients who are hepatitis B surface antibody–positive with detectable HBV DNA and elevated transaminase levels are candidates for treatment. Several guidelines have been published for the correct management and treatment of coinfected patients. Adequate workup of clinical and laboratory parameters, as well as pathologic staging and grading, is recommended before initiation of therapy. The histologic picture is that of chronic hepatitis with the characteristics of HBV infection ( Fig. 17.5 ); there may be a variable degree of steatosis.