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Quantitative Hepatic Function Predicts Outcomes of Chronic Liver Disease

  • Authors: John C. Hoefs, MD
  • CME Released: 10/28/2014
  • Valid for credit through: 10/28/2015
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Target Audience and Goal Statement

This activity is intended for gastroenterologists and hepatologists who provide care for patients with chronic liver disease.

The goal of this activity is to increase awareness of the value of assessing quantitative liver function to predict outcomes in patients with chronic liver disease.

Upon completion of this activity, participants will be able to:

  1. Summarize the benefits and limitations of methods used to predict clinical outcomes in patients with chronic liver disease


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  • John C. Hoefs, MD

    Professor Emeritus of Medicine, University of California at Irvine, Orange, California


    Disclosure: John C. Hoefs, MD, has disclosed the following relevant financial relationships:
    Owns stock, stock options, or bonds from: HEPATIQ LLC

    Dr Hoefs does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Hoefs does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Susan L. Smith, MN, PhD

    Lead Scientific Director, Medscape, LLC


    Disclosure: Susan L. Smith, MN, PhD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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Quantitative Hepatic Function Predicts Outcomes of Chronic Liver Disease

Authors: John C. Hoefs, MDFaculty and Disclosures

CME Released: 10/28/2014

Valid for credit through: 10/28/2015


  • Hello, I am Dr John Hoefs, a hepatologist and professor emeritus at the University of California Irvine. Welcome to this program titled "Quantitative Hepatic Function for Predicting Outcomes in Chronic Liver Disease." I am going to describe a technique for the precise measurement of hepatic function that is predictive of both short-term and long-term outcomes. Before I begin I would like to mention that this program includes a discussion of devices and diagnostics not approved by the United States Food and Drug Administration.

    I'm going to talk about a technique for quantitative measurement of hepatic function. In fact, it is a very useful technique for predicting poor clinical outcomes (referred to throughout as "clinical events") in patients with chronic liver disease. I am going to take you through how this technique was developed and summarize clinical trial data that show how valuable this technique is. I will also compare the use of quantitative hepatic function with methods used to stage hepatic fibrosis to determine perfused hepatic mass (PHM).

  • Slide 1.

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  • What is chronic liver disease? Chronic liver disease is the gradual accumulation of scar tissue or fibrosis within the liver. Fibrogenesis usually occurs as the result of inflammation, such as occurs with chronic hepatitis C or hepatitis B infection. Fibrogenesis is progressive, leading to decreased hepatic function, portal hypertension, and hepatic carcinogenesis. Fibrosis is a small amount of scar tissue, and usually is not associated with clinical problems, whereas cirrhosis is a larger amount of scar tissue and it is at this stage that most of the clinical problems and abnormal liver test results occur. Scoring of fibrosis by liver biopsy is very helpful, but hardly perfect, and it is limited by the size of the tissue sample and the fibrosis scoring system used. For example, an Ishak score of 0 to 4 indicates fibrosis and an Ishak score of 5 or 6 indicates cirrhosis, and then there are finer determinations once cirrhosis occurs.[1]

  • Slide 2.

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  • Historically, liver disease has been staged based on the amount of hepatic fibrosis. The picture in the upper left of the slide is of a cirrhotic liver. The white areas between the bumps are scar tissue, the bumps are actually the good tissue. We see the same thing at peritonoscopy in a live patient. On the right side of the slide, 2 liver biopsy specimens from the same patient are shown, one with a hematoxylin and eosin stain (specimen on left) and the other with a trichrome stain (specimen on right). In the trichrome-stained specimen, the tissue stained blue is scar tissue and the tissue stained pink is the functioning tissue. My question is, Do we really want to know how much fibrosis is present or more importantly, do we want to know how much functioning tissue is present? Is the latter not more predictive of patient outcome than the amount of scar tissue? There is a variable relationship between fibrosis and functioning tissue, depending on the type of liver disease and cofactors.

  • Slide 3.

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  • The major methods used to score histologic staging of hepatic fibrosis are the METAVIR system[2] and the Ishak system.[1] The Ishak system is more useful, but the METAVIR system is used more often. The METAVIR system includes only 1 stage for cirrhosis, yet this is where the important changes occur and there are actually several phases of cirrhosis: early, middle, and late. Most of the clinical problems occur in the late phase, yet all of the phases are combined in the METAVIR system. The Ishak scoring system is more useful because it includes 2 scores for cirrhosis: 5 and 6. This slide shows the limitations of these methods of staging fibrosis.

    Editor's Note: The Ishak staging system is a modification of the Knodell system (which lacks a stage 2) and has 6 stages of fibrosis (0-6).[1] The Ishak staging system has become widely used in clinical trials, especially in the United States. Because each Ishak fibrosis stage reflects more scarring than the preceding stage, clinicians and investigators assume that succession from one stage to the next represents progressively more advanced liver disease.

  • Slide 4.

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  • My focus is on hepatic function and I want to reiterate that decreased hepatic function is not proportionate to the amount of hepatic fibrosis; it is more closely associated with clinical problems, such as the need for liver transplantation, and death. A histologic specimen does not tell the whole story. The difference between early and advanced cirrhosis is the amount of functioning liver tissue. When it is determined that cirrhosis is present, it is important to predict how the patient will do over time, and to do this we need a precise measure of hepatic function. In addition, approximately 5% to 10% of patients with cirrhosis have normal hepatic function when first detected and they do very well. Therefore, knowing the degree of hepatic function is more helpful than knowing the degree of hepatic fibrosis.

  • Slide 5.

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  • The X axis on this slide shows the Ishak score,[3] which indicates the amount of scar tissue in the liver that accumulates over time. On the far right of the slide note that as fibrosis develops, clinical problems associated with altered hepatic function occur. The Y axis shows hepatic function, which remains relatively normal until cirrhosis is present, and then there is a progressive deterioration that correlates with abnormal hepatic function tests and the clinical problems that develop as a result of advanced liver disease.[4] On the bottom of the slide "Rf" indicates the rate of progression of fibrosis. A low Rf indicates a slower progression and a high Rf indicates more rapid progression. An Rf greater than .2 Ishak units per year indicates a very rapid rate of progression.[5]

  • Slide 6.

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  • The correlation between hepatic fibrosis and hepatic function is not linear. Hepatic fibrosis can be measured on liver biopsy as well as with newer techniques, such as FibroScan™ (which uses elastography), magnetic resonance imaging, and serum fibrosis tests. However, the problem with these methods is they do not measure hepatic function. Routine blood tests of hepatic function are not precise enough and they are affected by many variables; for example, the serum albumin level decreases with nephrotic syndrome. Therefore, hepatic function is better measured with quantitative tests, but in general these tests are complicated, time consuming for both providers and patients, and expensive. The quantitative liver and spleen scan (QLSS), a measurement of count (the amount or unit of uptake of radioactive substance) ratios in the liver, spleen, and bone marrow, is a much simpler and more widely available method compared with some other methods. The ideal quantitative hepatic function test would be simple, readily available to clinicians, precise and accurate, easy to interpret, suitable for serial studies, noninvasive, and not time consuming for the patient.

  • Slide 7.

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  • Quantitative tests of hepatic function are either blood flow-independent or blood flow-dependent. The aminopyrine breath test is a blood flow-independent test, but it is not as accurate as the blood flow-dependent tests. The classic blood flow-dependent test is the indocyanine green (ICG) clearance test and I'll mention that again later. But like the other blood flow-dependent tests shown on the slide, it is time consuming and requires special equipment to perform.

  • Slide 8.

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  • The QLSS, which measures uptake of technetium sulfur colloid (99Tc) in the liver, spleen, and bone marrow, is a precise measure of hepatic function.[6] Theoretically, there would seem to be a problem with the QLSS in that the injected sulfur colloid is taken up by the Kupffer cells in the liver (and thereby measures Kupffer cell mass), whereas hepatic function is dependent on hepatocytes.[6,7] So how does measurement of Kupffer cell mass reflect hepatic function?

  • Slide 9.

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  • The answer is, there is a fixed ratio of Kupffer cells to hepatocytes in the liver and the perfusion of both cell lines is equal. Therefore, the Kupffer cell mass is directly proportional to the functioning hepatocyte mass and thereby, liver function.[7] How does the QLSS measure hepatic function? The QLSS measures the distribution of 99Tc in the liver, spleen, and bone marrow. Uptake of 99Tc sulfur colloid by the bone marrow and the spleen are passive, an increase in uptake is primarily due to a decrease in liver uptake. Therefore, the ratios of measured units of 99Tc sulfur colloid (count ratios) in the liver/spleen and the liver/bone marrow reflect hepatic function. The size of the spleen also increases the total count in the spleen, so the liver-to-spleen ratio must be corrected for spleen size.

  • Slide 10.

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  • This slide shows the basic technique. The stacked slices in the center represent a 3-dimensional organ (in this case, the liver) that has been reconstructed by single-photon emission computerized tomography (SPECT) scanning. They have a relatively wide voxel or pixel (basic unit of 99Tc sulfur colloid detection) width. This 3-dimensional image is then summarized into a 2-dimensional image that includes all the counts in the respective organs (in this case, the liver). The region of interest (ROI) drawn around the 2-dimensional image reflects the total counts within the organ (in this case, the liver). These counts are very precise, within ± .01% on repeat measures. Therefore, the count ratios are precise.

  • Slide 11.

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  • This slide shows the QLSS technique. In preparation for the test, the patient is fed to maximize blood flow to the liver. Then, the 99Tc sulfur colloid is injected. After 20 minutes the data are obtained by the scanner and a SPECT reconstruction, which is a 3-dimensional image, is created. The 2-dimensional image that is then created is shown the lower left of the slide. The ROIs are constructed around those organs to determine the total counts. On the lower left of the slide the actual counts in those organs are shown. You can also see the posterior planar view from which the spleen length can be measured. This is used to correct the liver-spleen index (LSI), defined as ratio of counts or units of uptake of 99Tc sulfur colloid in the liver and spleen. Ratios of the LSI and liver-bone marrow index (LBI), defined as ratio of counts or units of uptake of 99Tc sulfur colloid in the liver and bone marrow, can be measured from the QLSS. The average of these indices (LSI and LBI) is the PHM, a measure of hepatic function that is very simple to obtain and very accurate.

  • Slide 12.

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  • Does the QLLS really measure hepatic function? This slide shows data from a very old paper in which we measured the redistribution ratio (RR), a semiquantitative measure of 99Tc sulfur colloid distribution in the liver, spleen, and bone marrow.[8] We compared the RR with the elimination rate constant for ICG, a dye that is a very good measure of hepatic function. These data from patients with alcoholic hepatitis were obtained on hospital admission and 1 month later. Some of the patients got worse and some got better, but at both times, redistribution of 99Tc sulfur colloid correlated very nicely with hepatic function. Therefore, 99Tc sulfur colloid redistribution is a test of hepatic function. Also, when we developed the PHM as a measure hepatic function, it correlated nicely with ICG clearance.

  • Slide 13.

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  • We looked at the PHM in 329 consecutive patients being assessed for liver disease.[6] The range of PHM values is large when patients with normal liver function (on the far left) and patients with chronic persistent hepatitis and minimal liver disease are included. The PHM range in those patients was relatively narrow and they had very good hepatic function. All abnormal PHM values occurred in patients with liver disease, alcoholic hepatitis, quiescent alcoholic liver disease, and nonalcoholic liver disease. In fact, there were no differences in PHM among these patients, regardless of the cause of liver disease.

  • Slide 14.

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  • What is the relationship between of PHM and various types of liver disease? It is severity. In this study the PHM correlated well with the Child-Pugh score, a traditional measure of severity; and as expected, there was a good correlation between the PHM and the amount of fibrosis.[6] However, as I will show, the PHM is a much better predictor of clinical liver disease than the Child-Pugh score or the fibrosis score.

  • Slide 15.

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  • This final preliminary study was conducted on livers explanted either at autopsy or at the time of liver transplantation in patients with various types of liver disease. We multiplied the percent of functioning liver tissue by the weight of the liver to determine the nonfibrotic weight, which is equivalent to the functioning mass of the liver, and compared that with the PHM, which is shown on the slide in this example as 55.[7] Note that this is a very sick group of patients based on the Child-Pugh score, bilirubin level, and prothrombin time.

  • Slide 16.

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  • This slide shows an almost perfect correlation between the PHM on the X axis and the nonfibrotic weight (the functional mass of the liver) on the Y axis.[7] Therefore, the PHM is a measure of functional liver mass in patients with chronic liver disease. Notably, all patients in this study had cirrhosis. I mentioned the correlation between hepatic function and hepatic fibrosis is not perfect. The patient with a PHM of 30 had hepatitis B virus infection and a very small liver. Her percent fibrosis was about 30%. The patient with the best hepatic function had alcoholic liver disease and a very large liver, with nearly 60% fibrosis. Therefore, there is not a good correlation between hepatic function and hepatic fibrosis, particularly among patients with different etiologies of liver disease.

  • Slide 17.

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  • The HALT-C trial was a prospective study of outcomes in 1050 patients with chronic hepatitis C virus infection and moderate fibrosis or cirrhosis who were followed for nearly 8 years.[9] The goal of the study was to determine if maintenance treatment with pegylated interferon alfa-2a would decrease clinical events in this patient population. Patients were treated at baseline with a lead in of long-acting pegylated interferon alfa-2a and ribavirin and were then randomized to treatment or no further treatment. Throughout the study patients were monitored for the development of ascites, hepatic encephalopathy, and other clinical problems.

  • Slide 18.

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  • A subset of patients (n=385) in the HALT-C trial had serial QLSSs.[3] The PHM was measured at baseline, 24 months, and 48 months. The aim was to determine if baseline PHM could predict clinical events over the next 8 years. We were also able to look at clinical outcomes in the 2 years following each scan. At baseline we asked whether there was an increase in clinical outcomes for the 2 years following that scan, and at month 24 we can did the same thing. We looked at both the prediction over a 2-year period, as well as the 8-year period of the study.

  • Slide 19.

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  • At baseline, patients were categorized into tertiles based on the PHM. The blue line at the bottom depicts the patients with the worst PHM. Nearly all of the clinical events occurred in this group; there was an approximate 15-fold increase in the risk for clinical events in this group compared with the other groups. When clinical events occurred in the other groups, they occurred relatively late and in patients who had a deterioration in the liver-spleen scan. Thus, PHM was predictive of clinical events in these groups as well.[3]

  • Slide 20.

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  • The bars on the left of this slide show patients categorized as either low risk or high risk based on PHM determined by QLSS. A PHM value (average of LSI and LBI) of less than 95 is considered high risk for clinical events. No clinical events occurred in the low-risk group, and essentially all clinical events occurred in the high-risk group, 22% over the first 2 years.[3] We then measured the PHM from the QLSS at 24 months (the bars on the right) to determine what happened over the next 2 years. Again, all clinical events (about 27%) occurred in the high-risk group. Therefore, the PHM predicted patients that were likely to have clinical events over the short term and the long term.

  • Slide 21.

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  • This slide is very illuminating. It shows serial PHM measurement by QLSS vs the development of clinical events over time.[3] The line at the top represents the group that did not develop clinical events. This group had a normal PHM at baseline and they had no deterioration in PHM over time; in fact, they improved. The take home message is clinical events do not develop in patients who do not show a deterioration in the PHM as measured by the QLSS. Therefore, serial studies in these patients are very helpful for predicting who is likely to develop clinical events. The 2 lines at the bottom represent groups with a relatively low PHM at baseline, in the range of 85. The bottom line (light blue) represents patients who developed clinical events within the first 24 months. Not only was the baseline PHM low in these groups, deterioration in PHM was relatively rapid. The baseline PHM was also low in the group that developed clinical syndromes between 24 and 48 months (shown by the red line), but deterioration occurred at a slightly slower rate in this group. Patients who developed clinical events after 4 years (shown by the green line) had better PHM at baseline than the previous group, and deterioration occurred at a much slower rate. I reiterate that if deterioration in the PHM as measured by the QLSS does not occur, clinical events will not develop.

  • Slide 22.

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  • My colleagues and I presented an abstract at The International Liver Congress in 2014, and the 49th annual meeting of the European Association for the Study of the Liver, in London, United Kingdom, April 9-13, 2014. We looked at PHM at 24 months and change in PHM from baseline to 24 months as predictors of clinical events. Both variables were shown by multivariate analysis to be independent predictors of outcome. In both the short term and the long term, the PHM is a very effective predictor of the development of clinical events.[10]

  • Slide 23.

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  • The A2ALL study showed an even shorter-term benefit of the QLSS. The rate of hepatic regeneration and functional recovery was studied in patients who donated two-thirds of their liver to someone who needed a liver transplant.[11] Multiple quantitative hepatic function tests were used. I am not going to go into detail on them, but I included the liver-spleen scan as noted by the gray lines at the bottom of the graph. The computed tomography-derived liver/volume ratio (liver volume after lobectomy vs liver volume at baseline) is shown on the Y axis. At baseline, the volume is 1 for all patients. In the lowest lines, we can see that 70% of the liver was removed by hepatectomy, so patients were left with only 30% of their liver. As we follow the lines up we can see that the liver volumes doubled in 2 weeks, reached about 90% of normal volume within 3 months, and were restored to normal volume within 6 months, as indicated by the red circles. The PHM is indicated by the yellow squares on the set of blue lines above the set of gray lines. Because there is an increase in tissue perfusion, liver function is actually restored faster than liver volume. Therefore, we showed very precisely that these patients did well based on quick restoration of liver function.

  • Slide 24.

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  • This slide shows serial PHM measurements in a patient with nonalcoholic steatohepatitis (NASH) and cirrhosis. He was markedly obese and had uncontrolled diabetes with a hemoglobin A1c (HbA1c) of 11. He refused to modify his diet or his sodium intake. When I first saw him he had poorly controlled ascites, mainly due to his sodium intake. He had an abnormal QLSS with a PHM of 72 to 74 that markedly deteriorated over the next couple of years. He developed hepatic encephalopathy, refractory ascites unresponsive to diuretics, and marked loss of muscle mass. He was eventually referred for liver transplantation, and when his PHM was in the range of 55, he was accepted for liver transplantation. However, as a result of his weight loss, his diabetes became controlled with an HbA1c of 6. He remained stable and his next PHM was 72. Subsequently, his clinical manifestations resolved and he was taken off the liver transplant list. He continues to do well. Reversal of NASH and cirrhosis was documented by serial QLSSs.

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  • What conclusions can we draw from these studies? First, the PHM is a precise measure of hepatic function. I did not present the data, but the spleen volume and hepatic volume are also precise measures of function. The PHM predicts clinical events very effectively and is suitable for serial studies. The use of the QLSS to measure the PHM has been limited to a given computer or scanner and therefore, this method has not been widely utilized, despite what its simplicity and effectiveness would suggest.

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  • Thank you for participating in this activity. We have appreciated your time and effort. We would like you to click on the "Earn CME Credit" link to revisit the question presented at the beginning of the activity to see what you have learned. The CME posttest and evaluation will follow. Thank you very much.

    This transcript has been edited for style and clarity.

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