OVERVIEW: What every practitioner needs to know
Are you sure your HIV patient has liver disease? What should you expect to find?
Patients are most likely to present with fatigue and possibly hepatomegaly and/or jaundice.
Scleral icterus – liver diseases of all kinds threaten the organ’s ability to keep up with bilirubin processing. Starvation, infections, certain medications, hepatitis, and cirrhosis can all cause hepatic jaundice, as can certain hereditary defects of liver chemistry, including Gilbert’s syndrome and Crigler-Najjar syndrome.
Hepatomegaly – an enlarged liver upon physical examination is found frequently in patients with liver disease and can reflect liver involvement from opportunistic infections or HIV-associated malignancies, but also derive from acute viral hepatitis, drug toxicity or metabolic disorder.
Fatigue – may accompany liver disease and most likely results from the inflammation in the liver regardless of origin.
Loss of appetite – is frequently found in patients presenting with concomitant liver disease.
Fever – is the rule in mycobacterial disease and other infections of the liver but not necessarily present in metabolic or drug toxicity associated liver disease unless the liver is involved in a hypersensitivity reaction such as with nevirapine or abacavir.
Ascites – may be found in decompensated cirrhosis and advanced liver disease but also during mycobacterial disease with liver involvement or malignancies of the liver.
Skin findings – chronic liver disease of any origin can cause typical skin findings. Jaundice, spider nevi, leukonychia (white finger nails) and finger clubbing are well known features of chronic advanced liver disease. Palmar erythema, rosacea and rhinophyma are also common but often overlooked. More subtle signs include scratch marks, loss of axillary hair and gynecomastia caused by an imbalance in sex hormones.
How did the patient develop liver disease/liver infection? What was the primary source from which the infection spread?
The liver can be affected by HIV in many different ways. Liver involvement can occur in various AIDS defining diseases (see below). With the advent of potent antiretroviral therapy these complications have declined dramatically. At present, drug-associated hepatotoxicity and viral hepatitides represent the main manifestations of liver disease in people living with HIV. In the setting of advanced immunodeficiency hepatitis B, C and D, progress is faster to cirrhosis.
As a consequence, the proportion of morbidity and mortality attributable to liver disease has increased substantially in HIV-coinfected individuals.
Atypical mycobacteriosis–HIV patients with advanced immunodeficiency and a CD4-count below 50 cells/µl are at increased risk for development of atypical mycobacteriosis. The most common species found in AIDS-patients is M. avium, usually diagnosed as M. avium-intracellulare complex. Mycobacteria can colonize the lungs and then enter the bloodstream and spread throughout the body presenting as disseminated disease with frequent involvement of the liver, spleen, and intraabdominal lymph nodes. Symptoms include fever, night sweats, weight loss, appetite loss, fatigue, and progressively severe diarrhea, stomach pain, nausea, and vomiting.
Other opportunistic infections – Many AIDS defining opportunistic infections can also involve the liver: Disseminated fungal infections such as histoplasmosis and cryptococcosis, and more rarely microsporidiosis and cryptosporidiosis. Extrapulmonary infection of the liver with pneumocystis jirovecii has been reported in a few cases, particularly in patients who were on pentamidine PjP-inhalation prophylaxis.
CMV hepatitis – At least 60% of the US population has been exposed to CMV, with a prevalence of more than 90% in high-risk groups (e.g., men who have sex with men [MSM]). CMV is transmitted from person to person via close contact. It can be spread through the placenta, blood transfusions, organ transplantation, breast milk and sexually. Clinically significant CMV disease (reactivation of previously latent infection or newly acquired infection) frequently develops in patients immunocompromised by HIV infection and can present as CMV hepatitis.
Hepatitis A – The modes of transmission are mostly ingestion of contaminated water and food, such as raw clams or oysters, oral-anal contact, person-to-person spread via shared utensils or bath towels; or, very rarely, blood or blood product transfusion. MSM are at an increased risk for hepatitis A virus (HAV) infection. HAV does not seem to cause more severe clinical illness in HIV-infected individuals; however, acute HAV may require temporary interruption of antiretroviral (ARV) therapy, which has potential long-term consequences.
Hepatitis B – Due to shared routes of transmission, many patients infected with HIV have markers of past exposure to hepatitis B virus (HBV). Chronic HBV infection currently affects 5-10% of individuals with HIV infection in developed countries, despite HBV vaccination being widely available. Acute hepatitis B has become rare because of increased uptake of HBV vaccination programs. Flares of HBV may occur in patients with previously resolved HBV infection, particularly during HAART interruptions or during chemotherapy for malignancies.
Hepatitis C – HCV and HIV are both transmitted by blood and blood products with HCV being 10 times more infectious than HIV. Coinfection with HIV and hepatitis C is therefore frequent in persons with blood exposure. Thus, chronic hepatitis C can be found in 60-90 % of HIV-positive hemophiliacs and 50-70% of HIV-positive intravenous (IV) drug users. In contrast, sexual transmission of HCV is rare, which explains the low (4-8%) frequency of HCV coinfections in homosexual HIV patients. Small epidemics of acute HCV have been reported in men who have sex with men in European and North American cities, associated with a high number of sexual partners and sexual practices involving exposure to blood.
HIV associated malignancies – Kaposi’s sarcoma (KS) as well as lymphoma (both Hodgkin’s and non-Hodgkin’s lymphoma) can present as AIDS defining malignancies with liver involvement. When involving the liver, KS is already well established on skin and mucosa. Lymphoma in contrast can often present first in the liver.
Which individuals are at greater risk of developing liver disease?
Immunodeficiency – Antiretroviral-naïve HIV patients with a CD count less than 200/µl are at increased risk for development of AIDS defining events including opportunistic infections with liver involvement. Whereas tuberculosis can also occur at higher CD4 counts, the median CD4 count in patients with atypical mycobacteriosis is less than10/µl. AIDS defining malignancies can occur at any CD4 count but are much more frequent in patients with more advanced immunodeficiency.
Underlying liver disease – Patients with underlying chronic hepatitis B or C or alcoholic liver disease are at increased risk for hepatotoxicity after initiation of antiretroviral therapy and can develop grade 3-4 liver enzyme elevations.
In hepatitis B – HIV coinfection, hepatitis B may flare in the months after starting ART, particularly in the setting of more pronounced immune reconstitution.
Patients who are not vaccinated remain at high risk for contracting hepatitis A and B, underlining the need for vaccination in this particular patient group. Outbreak of acute hepatitis C in MSM warrants monitoring, especially when sexual practices involve exposure to blood.
Beware: there are other diseases that can mimic HIV associated liver disease:
Cholecystitis, cholangitis, and cholelithiasis
Malignancies of the bile duct system
Non-alcoholic fatty liver disease
Alcoholic liver disease or alcohol hepatitis
Budd Chiari syndrome
What laboratory studies should you order and what should you expect to find?
Results consistent with the diagnosis
An initial step in detecting liver damage is to determine the presence of liver enzymes in the blood. Under normal circumstances, these enzymes reside within the cells of the liver. But when the liver is injured, they spill into the blood stream. Among the most sensitive and widely used of these liver enzymes are the aminotransferases. They include aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT). The ACTG grading of liver enzyme elevations is listed in Table I.
The prevailing pattern of lab abnormalities allows to further differentiate different causes of liver disease. Acute cytolytic damage is characterized by high ALT or ALT/Alkaline phosphatase (AP) greater than 5, whereas acute cholestatic damage shows high AP or ALT/AP less than 2. A mixed pattern shows high ALT and AP or ALT/AP between 2 and 5.
Bilirubin is measured to diagnose and/or monitor liver diseases such as cirrhosis, hepatitis, or cholestasis due to gallstones. Bilirubin which is bound to glucuronide to form conjugated bilirubin is called direct bilirubin. Unbound bilirubin is also referred to as indirect bilirubin. Jaundice may be noticeable in the sclera (white) of the eyes at levels of about 2 to 3 mg/dL (34 to 51 μmol/L) and in the skin at higher levels. Increased total or unconjugated bilirubin may be a result of hemolytic anemias.
If conjugated bilirubin is elevated, there may be some kind of blockage of the liver or bile ducts, hepatitis, trauma to the liver, cirrhosis, a drug reaction, or long-term alcohol abuse. Inherited disorders of the bilirubin metabolism such as Gilbert’s disease can result in mild jaundice, found in about 5% of the population. Unconjugated hyperbilirubinemia caused by competitive inhibition of the uridine diphosphate-glucuronosyl transferase (UGT) 1A1 enzyme can be found during atazanavir or indinavir treatment and is particularly pronounced in patients with underlying Gilbert’s syndrome.
Alkaline phosphatases (AP) are a group of enzymes found primarily in the liver. When the liver, bile ducts or gallbladder system are not functioning properly or are blocked, AP is not excreted through the bile but released into the blood stream. Thus, the serum AP is a measure of the integrity of the hepatobiliary system and the flow of bile into the small intestine. It is typically increased in atypical mycobacteriosis but can also increase during other opportunistic infections affecting the bile duct system such as microsporidiosis or cryptosporidiosis.
International normalized ratio
The international normalized ratio (INR) is a test of blood clotting, which is primarily used to monitor warfarin therapy. In the context of liver disease the INR is a reliable test for liver synthetic function. Indeed INR has evolved over the past 2 decades as a key measure of assessing bleeding risk in liver disease. Moreover, it is one contributing laboratory parameter in the CHILD PUGH classification, which is used to assess the prognosis of chronic liver disease, mainly cirrhosis (see Table I). A total score of 5-6 is grade A (well-compensated disease); 7-9 is grade B (significant functional compromise); and 10-15 is grade C (decompensated disease). These grades correlate well with survival.
Albumin is a protein made by the liver. Albumin levels are decreased in chronic liver disease, such as cirrhosis. It is also decreased in nephrotic syndrome, where it is lost through the kidney. Albumin is also a laboratory parameter which is included in the CHILD-Pugh score (see Table II). However, coagulation factors are much more sensitive for assessment of liver synthetic function.
Results that confirm the diagnosis
Viral hepatitis testing
Viral hepatitis can be diagnosed by serologic and molecular markers which are summarized for the five most important forms of hepatitis in
Diagnosis of acute hepatitis A is based on the detection of anti-HAV IgM antibodies. Isolated HAV-IgG antibodies are indicative of resolved infection or past vaccination.
Chronic HBV infection is defined as detectable HBS-Ag for more than 6 months. In acute HBV infection HBc-IgM antibodies can be found. Detection of anti-HBs and anti-HBc antibodies is indicative of resolved prior infection and sole presence of anti-HBs-antibodies a sign for successful prior vaccination. The presence of only anti-HBc antibodies suggests occult HBV infection. In cases of advanced immunodeficiency with very low CD4 counts, loss of anti-HBs antibodies may occur, and this would warrant additional HBV-DNA testing. HBV-DNA can be measured quantitatively and is a marker of viral replication.
More recently, quantitative HBs-Ag measurements have been shown to be extremely useful in monitoring how well patients are responding to HBV therapy with interferon. Indeed quantitative measurement of change (or lack of change) in HBsAg levels as early as 12 weeks under a pegylated interferon based HBV therapy can predict its success as late as 5 years post-treatment.
In case of suspected acute HCV in a HIV-coinfected individual up to 6 months (in rare cases even longer; 5% are still antibody-negative after 12 months) can pass until HCV antibodies become detectable. Therefore HCV-RNA determination is important in order to make the diagnosis of acute HCV. In patients with HCV-antibodes but repeatedly negative HCV-RNA, resolved HCV infection must be presumed. A positive HCV RNA is indicative of chronic replicative disease.
A HDV infection absolutely requires an associated HBV infection. The diagnosis of acute hepatitis D is made after evaluation of serologic tests for the virus. Total anti-HDV is detected by commercially available radioimmunoassay (RIA) or enzyme immunoassay kits. The method of choice for the diagnosis of ongoing HDV infection should be RT-PCR, which can detect 10 to 100 copies of the HDV genome in infected serum.
Hepatitis E can be diagnosed by blood tests which detect elevated antibody levels of specific antibodies to hepatitis E or by reverse transcriptase polymerase chain reaction (RT-PCR). The highest rates of infection occur in regions where low standards of sanitation promote the transmission of the virus. Epidemics of hepatitis E have been reported in Central and South-East Asia, North and West Africa, and in Mexico. So far reports of hepatitis E in HIV patients other than in travelers have been rare, but chronic hepatitis E occurs in immunosuppressed individuals.
Alpha-fetoprotein (AFP) is a protein normally made by the immature liver cells in the fetus. At birth, infants have high levels of AFP, which fall to normal adult levels by the first year of life. Generally, in the adult normal levels of AFP are below 10 ng/ml. Moderate levels of AFP can be seen in patients with chronic hepatitis. Sudden increases as well as high levels of AFP are suggestive of liver cancer. Indeed, an elevated AFP blood test can be found in about 60% of liver cancer patients.
Biopsy of the liver establishes diagnosis of liver disease, and the severity of known liver disease, and can be used to monitor the effect of treatment. Particularly in HIV patients with advanced immunodeficiency and suspicion of an ongoing opportunistic infection with liver involvement, liver biopsy can be extremely helpful to establish diagnosis. For example histological evidence of granuloma and PCR can help to distinguish tuberculosis from atypical mycobacteriosis.
CMV staining can reveal CMV-hepatitis. Advanced stages of fibrosis in HIV infected individuals with chronic viral hepatitis are the basis for treatment interventions. Biopsy may help to differentiate between flare of underlying chronic viral hepatitis or drug toxicity.
What imaging studies will be helpful in making or excluding the diagnosis of liver disease?
Ultrasound of the abdomen- Ultrasound remains, based on easy access and low cost, the first-line imaging method of choice. The ultrasound of the liver can check the size, shape and position of the liver. An ultrasound will also provide information on causes of jaundice, presence of cirrhosis, fatty liver disease or liver masses. In addition, one can look for ascites and check for signs of portal hypertension and blood flow within the portal vein.
CT and MRI – CT and MRI are applied whenever ultrasound imaging yields vague results. Indications are the characterization of metastases and primary liver tumors e.g., benign lesions such as focal nodular hyperplasia (FNH), adenoma, hemangioma and malignant lesions such as hepatocellular carcinomas (HCC). CT is less costly and more widely available but has the disadvantage of radiation exposure. MRI is more sensitive for detection of small focal lesions in the liver and also allows reliably the identification of hemangioma which is a clear advantage over CT imaging.
Fibroscan – A fibroscan can measure the “stiffness” or “elasticity” of the liver, using an ultrasound scan to create waves and measure their speed. The wave speed is used to determine liver stiffness; the harder the liver tissue, the more rapidly the waves will pass through it. This scan is much less sensitive than biopsy to detect mild or moderate liver damage, but it is very sensitive at picking up severe damage. It can therefore identify people who need HCV treatment more urgently. Results are presented as kilopascals (kPa). The higher the figure, the stiffer and more damaged the liver. Overall, a score of over 7.2kPa indicates higher likelihood of significant fibrosis (F2 or greater on Metavir) and over 13kPa indicates cirrhosis (F4 on the Metavir scale).
Upper GI endoscopy – Every patient with more advanced stages of liver fibrosis, and in particular cirrhosis, should undergo upper endoscopy to check for esophageal varices. When esophageal varices are discovered, they are graded according to their size, as follows:
Grade 1 – Small, straight esophageal varices
Grade 2 – Enlarged, tortuous esophageal varices occupying less than one third of the lumen
Grade 3 – Large, coil-shaped esophageal varices occupying more than one third of the lumen
The esophageal varices are also inspected for red wheals, which are dilated intra-epithelial veins under tension and carry a significant risk for bleeding. The grading of esophageal varices and identification of red wheals by endoscopy predicts a patient’s bleeding risk, on which treatment (i.e. ligation, banding etc.) is based.
What consult service or services would be helpful for making the diagnosis and assisting with treatment?
If you decide the HIV patient has liver disease, what therapies should you initiate immediately?
No specific treatment exists for hepatitis A. Symptomatic treatment of nausea or dehydration may be warranted.
Indication for treatment of hepatitis B depends on level of HBV replication, live enzyme elevation and presence of cirrhosis. Patients with cirrhosis are immediate candidates for HBV therapy independent from other markers. Cirrhotic patients should be referred for variceal assessment, have regular monitoring for hepatocellular carcinoma (HCC; includes AFP measurement and ultrasound of the liver every 6 months) and be referred early for transplant assessment. Patients with liver cirrhosis and low CD4 counts require careful surveillance in the first months after starting HAART in order not to overlook immune-reconstitution syndrome and subsequent liver decompensation. Patients with elevated liver transaminases and levels of HBV-DNA > 2000 IU/ml should also be offered HBV therapy, whereas patients with normal transaminases and low level viremia can be followed with regular monitoring, but without treatment. HBV-infected patients requiring HAART, particularly with advanced liver fibrosis (F3/F4), should receive tenofovir (TDF) +3TC or FTC.
Figure 1 summarizes the current HBV treatment algorithm from the EACS guidelines. Co-infected patients without an indication for treatment of their HIV infection (CD4 > 500/µl) are generally eligible for therapy with pegylated interferon, although little data is available on its efficacy in HIV/HBV co-infection. In general, it seems reasonable to expect lower response rates. In HBV-monoinfection positive predictors for successful seroconversion are infection with wildtype HBeAg, HBV genotype A, distinctly elevated liver enzymes, and a low hepatitis B viral load. Proposed treatment duration for Peg-INF is 48 weeks.
If tenofovir is contra-indicated, entecavir + adefovir may be tried, or tenofovir in doses adjusted to renal clearance in combination with effective HAART may be used. NRTI substitution should only be performed if feasible and appropriate from the perspective of maintaining HIV suppression. Caution is warranted when switching from a tenofovir-based regimen to drugs with a lower genetic barrier, e.g. FTC/3TC, in particular in lamivudine-pretreated cirrhotic patients, as viral breakthrough due to archived YMDD mutations has been observed. This has also been described in individuals with archived lamivudine resistance who have been switched from tenofovir to entecavir.
The combination of Peg-INF alpha and ribavirin (RBV) is the treatment of choice for HCV infection. The standard dose for Peg-INF 2a is 180 μg once weekly, and for Peg-INF 2b it is 1.5 μg/kg bodyweight once weekly. An initial weight-adapted dose of RBV of 1000 (wt ≤ 75kg) -1200 (wt > 75kg) mg/day, administered in two doses per day, is recommended for all HCV genotypes. Duration of therapy depends on prevailing HCV genotype and rapidness of responding to therapy (see
Boceprevir and telaprevir are direct-acting agents (DAAs) against HCV; they have become available in 2011 for patients with HCV mono-infection. In HIV/HCV co-infection their use is complicated by drug-drug interactions and overlapping toxicity. At the current time, it is difficult to give definitive recommendations regarding their use. Factors to be considered are the following:
HAART improves the prognosis not only of HIV, but also of HCV (plus 2 NRTIs) infection. Particularly in co-infected patients with low CD4 counts, optimization of HAART is the first priority.
Co-infected patients, in particular former intravenous drug users, are frequently infected with HCV genotype 1. While this genotype responds less well to therapy with peginterferon and ribavirin than genotypes 2 and 3, it is also less virulent with regard to the progression of liver disease to fibrosis and cirrhosis. In view of the rapid progress in HCV therapy and the probable availability of less toxic and more effective drugs within the next few years, watchful waiting may be the best option for many co-infected patients.
If good prognostic factors are present, such as low HCV viremia (< 400000 copies/ml) in combination with the IL28B CC genotype, consider using peginterferon plus ribavirin without DAAs.
If treatment with boceprevir or telaprevir is planned, consider replacing HIV protease inhibitors, or efavirenz, with raltegravir (because raltegravir has minimal drug-drug interactions). As a rule of thumb:
HIV/HCV co-infected patients who are on raltegravir (plus 2 NRTIs), or who are not on anti-HIV drugs, may use boceprevir or telaprevir at standard doses
Patients who receive atazanavir with or without ritonavir (plus 2 NRTIs) may use telaprevir at standard doses but should avoid boceprevir
Patients who receive efavirenz may use telaprevir at the higher dose of 1125mg every 8 hours but should also avoid boceprevir
In patients with Delta virus co-infection and significant liver fibrosis (>F2) long-term (>18 months), treatment with pegylated interferon might be considered in association with tenofovir based HAART. TDF has shown some efficacy, especially in patients with detectable serum HBV-DNA. Treatment efficacy should be monitored with: HBV-DNA and HDV-RNA measurement, when available, and with follow-up of biochemical and liver fibrosis estimates.
As no specific therapy is capable of altering the course of acute hepatitis E infection, prevention is the most effective approach against the disease. Hospitalization is required for fulminant hepatitis and should be considered for infected pregnant women.
When administering therapy for atypical mycobacteriosis please check for corresponding drug-drug interactions and necessary dosage adaptations (for example reduction in rifabutin dose to 150mg every second day in combination with most boosted HIV protease inhibitors. Table III lists preferred treatments.
Hepatitis is commonly observed in patients with primary CMV infection and usually recovers without treatment. CMV hepatitis in HIV patients with more advanced immunodeficiency may also occur and in the setting of advanced immunosuppression may warrant anti-CMV therapy with ganciclovir or valganciclovir.
What's the evidence?
Joshi, D, O’Grady, J, Dieterich, D, Gazzard, B, Agarwal, K. “Increasing burden of liver disease in patients with HIV infection”. Lancet. vol. 377. 2011. pp. 1198-209.
Lacombe, K, Rockstroh, J. “HIV and viral hepatitis coinfections: advances and challenges”. Gut. vol. 61. 2012. pp. i47-58.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your HIV patient has liver disease? What should you expect to find?
- How did the patient develop liver disease/liver infection? What was the primary source from which the infection spread?
- Which individuals are at greater risk of developing liver disease?
- Beware: there are other diseases that can mimic HIV associated liver disease:
- What laboratory studies should you order and what should you expect to find?
- What imaging studies will be helpful in making or excluding the diagnosis of liver disease?
- What consult service or services would be helpful for making the diagnosis and assisting with treatment?
- What's the evidence?