[NATAP] Liver Disease in HIV

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Liver Disease in HIV

This study was published in 2001 & found that patients with lactic acidosis due to nukes also had symptoms found in fatty liver. But, a number of studies recently find lipid elevations and diabetes associated with fatty liver, which can lead to fibrosis (liver disease) and cirrhosis.

“Symptomatic Lactic Acidosis in Hospitalized Antiretroviral-Treated Patients with Human Immunodeficiency Virus Infection: A Report of 12 Casesâ€

Clinical Infectious Diseases Dec 2001;33:1914-1921

E. Coghlan,1 Jean-Pierre Sommadossi,2 Nirag C. Jhala,3 Wickliffe J. Many,1 S. Saag,1 and A. 1,4

Departments of 1Medicine, 2Pharmacology and Toxicology, and 3Anatomic Pathology, University of Alabama at Birmingham School of Medicine, and the 4Birmingham Veterans Affairs Medical Center, Birmingham, Alabama

ABSTRACT

We retrospectively investigated the clinical and histopathologic features of hospitalized patients infected with human immunodeficiency virus who had symptomatic lactic acidosis syndrome at a university teaching hospital during 1995-2000.

Twelve patients were identified, 11 during 1998-2000; of these, 5 died with rapid progression to otherwise unexplained multiple-organ failure. All had extensive prior exposure to nucleoside analog reverse-transcriptase inhibitors (NRTIs). At presentation, the most commonly identified NRTI component of antiretroviral regimens was stavudine plus didanosine.

Eleven patients presented with abdominal pain, nausea, and/or emesis. Eight patients had prior acute weight loss (mean [±SD], 12 ± 5.3 kg). Median venous plasma lactate levels were >2-fold greater than the upper limit of normal (2.1 mmol/L). Serum transaminase levels were near normal limits at presentation.

None had a history of significant liver disease or concurrent hepatitis B or C virus infection. Symptoms and signs were similar to those reported previously: nausea, emesis, abdominal pain, and distension associated with elevated venous plasma lactic acid levels, elevated liver function tests, and hepatic steatosis. The history of alcohol consumption, a known cause of limited hepatic reserve and steatosis, was known for all patients. For 10 patients, there was no history of alcohol consumption. One nonsurvivor had a remote history of modest alcohol consumption, and 1 survivor had a history of intermittent alcohol intake. One nonsurvivor and 1 survivor had diabetes mellitus, a risk factor for hepatic steatosis.

Lifetime NRTI experience in these patients was considerable. At presentation, 1 patient was receiving monotherapy with zidovudine, and 11 patients were receiving dual NRTI-containing highly active antiretroviral therapy regimens. Four were receiving concomitant hydroxyurea therapy. The most commonly identified 2-drug combined NRTI regimen was stavudine plus didanosine (9 patients, 4 of whom were on concomitant hydroxyurea and survived). The median lifetime number of antiretroviral regimens was 3 (range, 1-10). The median total duration of lifetime antiretroviral exposure was 21 months (20 months for survivors vs. 22 for nonsurvivors; P = .68; range, 6-70 months). The median total duration of lifetime NRTI treatment was 21 months (20 months for survivors vs. 22 for nonsurvivors; P = .68). Eleven patients had prior stavudine exposure. The median total duration of lifetime stavudine treatment was 16 months (17 months for survivors vs. 8 for nonsurvivors; P = 1.00). The median total duration of lifetime treatment with nonnucleoside analog reverse-transcriptase inhibitors was 0 months (range, 0-15 months). The median total duration of lifetime hydroxyurea therapy was 1 month for survivors (range, 0-11 months); none of the nonsurvivors had received hydroxyurea therapy. The median total duration of lifetime protease inhibitor (PI) therapy was 12 months (range, 0-46 months; 13 months for survivors vs. 0 for nonsurvivors; P = .21). Three of 7 survivors were receiving PI therapy; in contrast, only 1 of 5 nonsurvivors was receiving concurrent PI therapy (P = .58).

Histopathologic studies. Histopathologic studies of liver tissue samples obtained from 6 patients demonstrated macrosteatosis and microsteatosis by light microscopy; photomicrographs from 2 specimens are depicted in figure 1. Four autopsy liver specimens had 25%-90% macrosteatosis and & les;70% microsteatosis. Two liver biopsy specimens had 〜50% macrosteatosis and 30%-50% microsteatosis. Macrosteatosis was predominantly perivenular, whereas microsteatosis was more diffuse. Bile ducts were well preserved. One autopsy sample showed mild steatohepatitis, which suggested a possible preexisting liver dysfunction. There was minimal neutrophilic and lymphocytic inflammation, which was usually portal in location. Only 1 specimen showed focal areas of confluent necrosis. Special staining revealed no evidence of concurrent infections in any of the tissue samples examined.

Histopathologic studies confirmed hepatic macrovesicular and microvesicular steatosis in 6 patients. Concurrent chemical pancreatitis was identified in 6 patients. The increasing number of cases identified during the study period suggests that physicians better recognize symptomatic lactic acidosis and/or that cumulative NRTI exposure may increase the risk for this syndrome.

Carr et al. reported a syndrome of lipoatrophy, fatigue, nausea, weight loss, and hepatomegaly associated with lactic academia.

INTRODUCTION

Nucleoside analog reverse-transcriptase inhibitor (NRTI) therapy for chronic HIV infection has been associated with drug-induced toxicities. A clinical syndrome designated "type B lactic acidosis" (i.e., without hypoxemia), which is associated with mitochondrial myopathy, hepatic macrovesicular and microvesicular steatosis (hereafter, macrosteatosis and microsteatosis, respectively), lipoatrophy, liver dysfunction and/or fulminant liver failure, and occasional concomitant pancreatitis, has been associated with HIV NRTI therapy [1-9]. A standardized case definition for this syndrome has not yet been defined. The exact mechanism or mechanisms are unclear, but the syndrome appears to reflect mitochondrial damage in specific tissues that are affected at the cellular level [10, 11].

The aim of this study was to investigate the clinical features and histopathologic findings of clinically identified cases of symptomatic lactic acidosis among HIV-infected individuals treated with antiretrovirals and hospitalized at our institutions. In this case series, we also sought to present key clinical findings for patients who either survived or died during hospitalization.

AUTHOR DISCUSSION

This retrospective case series presents clinical, radiographic, and histopathologic manifestations of symptomatic lactic acidosis in 12 hospitalized patients infected with HIV who had been treated with antiretrovirals. An increasing number of cases were identified during 1995-2000, which suggests enhanced physician recognition and/or evidence that cumulative NRTI exposure may increase risk for the syndrome. Symptoms and signs were similar to those reported previously: nausea, emesis, abdominal pain, and distension associated with elevated venous plasma lactic acid levels, elevated liver function tests, and hepatic steatosis. Tachypnea and dyspnea were not as helpful diagnostic signs as has been reported elsewhere [1-3, 5, 8], because these symptoms did not identify high-risk patients early but rather signaled worsening preterminal lactic acidosis. Elevated venous plasma lactic acid levels and serum anion gaps were critical for making the clinical diagnosis. Indeed, there was a trend toward mortality for the group of patients who experienced greater changes in each of these laboratory parameters during hospitalization. However, other laboratory and radiographic parameters were not very helpful in discerning the clinical course. Serum transaminase levels were nearly normal at presentation and were not as predictive of the lactic acidosis syndrome as has been reported elsewhere [9]. The minimal inflammation histopathologically mirrored the relatively normal serum transaminase levels seen at presentation and the modest elevations observed during hospitalization; this finding is analogous to that described for cases of fialuridine-associated hepatic failure and lactic acidosis [4]. Interestingly, higher body mass indices were evident in our nonsurvivors. Although the exact significance of this finding is unknown, it is possible that preexisting steatosis related to comorbid obesity may increase the risk of drug-induced hepatic dysfunction and development of lactic acidosis. Concurrent chemical pancreatitis was identified in 6 patients.

It has been hypothesized that mitochondrial damage is a cause of the NRTI-associated lactic acidosis syndrome and that mitochondrial changes within adipocytes may result in a recently described NRTI-associated lipodystrophy syndrome [8, 14]. Carr et al. [8] reported a syndrome of lipoatrophy, fatigue, nausea, weight loss, and hepatomegaly associated with lactic acidemia. Chariot et al. [6] also described a single subject who had a progressive 20% weight loss before the onset of fatal zidovudine-associated lactic acidosis. In our cohort, 66% of patients also experienced a syndrome that suggested acute lipoatrophy immediately prior to hospitalization, with evidence of weight loss and poorly defined malaise preceding the diagnosis of lactic acidosis. This weight loss may indicate bioenergetic mitochondrial dysfunction that appears before the expression of more-commonly recognized lactic acidosis symptoms. Susceptible patients with cumulative NRTI exposure may accumulate subclinical mitochondrial DNA mutations over time to a threshold level of mitochondrial dysfunction at which clinical symptoms develop. This may be analogous to the "threshold expression phenomenon" seen in congenital mitochondrial mutation disorders, whereby symptoms are expressed only after a critical percentage of mitochondria become dysfunctional [15]. Furthermore, patients who died despite discontinuation of antiretroviral therapy may have reached a "physiologic point of no return," possibly because of irreversible mitochondrial damage and poor reserve function.

Our case series represents an advanced end of the spectrum of NRTI-associated lactic acidosis syndrome, because our patients had symptoms sufficient to require hospitalization. Ten patients had historical nadir CD4+ T lymphocyte counts of <200 cells/mm3. Such patients may be at increased risk for NRTI-associated symptomatic lactic acidosis syndrome, which requires further study. Lonergan et. al. [16] described a cohort of 20 HIV-infected patients with evidence of a milder form of lactic acidosis that did not always require hospitalization. The mean CD4+ T lymphocyte count was 370 cells/mm3 (range, 25-1397 cells/mm3). Only 3 patients required hospitalization, and all survived. Earlier recognition of lactic acidosis with more immediate discontinuation of drug therapy may allow the disorder to be reversed and prevent the need for hospitalization [16, 17].

The most common 2-drug combined NRTI backbone regimen in our patients was stavudine plus didanosine. However, the impact of prior or cumulative NRTI exposure on development of lactic acidosis syndrome was also likely important, given that this exposure was considerable in our patients. Nonsurvivors may have had a greater net loss of mitochondria after years of antiretroviral use and not-yet identified mitochondrial genetic defects, all of which may lead to inexorable bioenergetic dysfunction. It has been difficult to correlate the results of in vitro NRTI mitochondrial toxicity studies with reports of in vivo effects. Nonetheless, numerous in vitro studies have shown multiple mitochondrial defects after cell exposure to NRTIs, including ultrastructural changes, alterations in oxidative phosphorylation and lactate production, and decreases in total mitochondrial DNA (mtDNA). NRTIs exhibit a range of affinities for human mitochondrial γ DNA polymerase [18-24]. Combined NRTI therapies may have increased mitochondrial effects by inhibiting multiple steps in the complex energy production cascade.

Hydroxyurea boosts intracellular levels of the 5′-triphosphate derivatives of stavudine and didanosine, perhaps exposing mitochondria to enhanced nucleoside-associated toxicities. Recently, several trials that investigated hydroxyurea in combination with other antiretroviral therapies were terminated early because of potentially enhanced NRTI toxicities; in particular, neuropathy, pancreatitis, and liver dysfunction [25, 26]. The precise role of hydroxyurea and of other non-NRTI antiretroviral therapies in the manifestation of antiretroviral toxicities, and in particular NRTI-associated lactic acidosis, remains uncertain.

Our study has numerous limitations related to its design as a retrospective review of clinical and histopathologic data from a small number of patients. The patients described here had symptomatic lactic acidosis syndrome, although there is still no definitive case definition. This series provides insight about clinical, laboratory, and histopathologic features associated with severe cases, but it is recognized that all asymptomatic and milder clinical presentations were likely missed. Venous plasma lactic acid levels were not obtained routinely during the study period; thus, a case-control study design could not be applied retrospectively. Partial data collection and interpretation biases were also probable, as was the possibility of incomplete medical records. Tissue specimens were only available for 6 patients, and they were not well enough preserved for electron microscopy to demonstrate mitochondrial disruption definitively.

In summary, during 1995-2000, we identified an increasing number of cases of the symptomatic lactic acidosis syndrome in patients infected with HIV who had been treated with antiretrovirals, which suggests enhanced physician recognition and/or cumulative toxicities. We found concurrent chemical pancreatitis in 6 patients and identified a clinical syndrome similar to lipoatrophy that occurred as an early component of symptomatic hyperlactatemia. Our study confirms other reported studies that have underscored the likely presence of significant mitochondrial toxicity in susceptible patients, despite normal laboratory parameters. Early recognition and discontinuation of antiretroviral therapies are probably essential to recovery. Earlier clinical diagnosis may require histopathologic correlation and better laboratory tests. Prospective studies are required to delineate the spectrum of NRTI-associated lactic acidosis syndrome, its prevalence, the underlying genetic and biochemical mechanism(s), and possible therapeutic interventions.