Video 1: Anatomy of the liver

The liver is the primary organ involved in regulating the composition of circulating blood.¹

It has 2 blood supplies, the hepatic artery and the portal vein.¹

The liver is divided into 4 lobes:¹

• Right
• Left
• Caudate
• Quadrate

The main building blocks of liver tissue are the liver lobules.

• They consist of rows of hepatocytes formed in a hexagon around the central vein.¹
• Sinusoids radiate out from the central vein.¹
• Portal triad, which includes a branch of the hepatic artery, the portal vein and the bile duct.¹

The hepatic sinusoids empty into the central vein and contain:

• Kupffer cells: phagocytic cells that can stimulate inflammation.²
• Hepatic stellate cells: store fat-soluble vitamins and secrete collagen.^3,4

References:

1. Tortora GJ and Derrickson B. The digestive system. In: Principles of Anatomy and Physiology. 14th ed. Hoboken, NJ: Wiley; 2014:909-913.
2. Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver. Compr Physiol. 2013;3(2):785-797. doi:10.1002/cphy.c120026
3. Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27-42. doi:10.1016/j.addr.2017.05.007
4. Wake K. Hepatic stellate cells: three-dimensional structure, localization, heterogeneity and development. Proc Jpn Acad Ser B Phys Biol Sci. 2006;82(4):155-164. doi:10.2183/pjab.82.155

 

 

Video 2: Fibrosis and cirrhosis of the liver

So what is liver fibrosis?

Liver fibrosis occurs because of persistent liver inflammation from a number of causes including alcohol abuse, autoimmune disorders, or viral infection: for example, hepatitis C.

Hepatitis C virus infection causes inflammation which stimulates liver cells to produce excessive extracellular matrix, which replaces the damaged cells.^1-3

Accumulation of extracellular matrix causes structural changes in the liver, eventually leading to liver disfunction and metabolic disruption.¹

Liver fibrosis progression is often nonlinear. It may progress quickly or progress slowly over years.

It is important to determine the extent of fibrosis as it can affect which healthcare practitioners are able to treat the patient for underlying causes, treatment options, and long-term liver cancer screening.

Staging of fibrosis

The degree of fibrosis in the liver can be divided into stages. One of the most common staging methods is known as METAVIR staging, in which fibrosis ranges from F0 to F4.^4-6

A normal, healthy liver with no fibrosis is known as fibrosis stage F0.^5,6

F1: Minimal fibrosis

This is the earliest stage of fibrosis, where there is very little fibrosis but portal triads expand.^5,6

F2: Moderate fibrosis

Fibrosis has progressed to form a small number of septa and some bridging occurs between expanded portal spaces. Scarring has built up around the blood supply to the liver.^5,6

F3: Advanced fibrosis

Numerous septa form, there is marked bridging, and some nodules form. The scars around different blood vessels in the liver are joined, but liver function is unaffected.^5,6

F4: Cirrhosis

Scarring has built up in the tissues of the liver and its function is impaired.^5,6

So, in summary, here’s a recap of how the liver’s affected at each stage.

• F0 No fibrosis
• F1 Minimal fibrosis
• F2 Moderate fibrosis
• F3 Advanced fibrosis
• F4 Cirrhosis

What is cirrhosis?

Cirrhosis refers to advanced liver disease at the end stages of fibrotic progression.^7-9

A cirrhotic liver is characterized by regenerative nodules surrounded by dense fibrotic tissue and by abnormal function.⁸

Cirrhosis can be classified by compensated or decompensated, depending on the extent of liver damage.

Cirrhosis increases the risk of liver cancer.^6,10

Patients with advanced fibrosis or cirrhosis are recommended for long-term follow-up and biannual liver cancer screening.⁴

Those with decompensated cirrhosis may be referred to a liver cancer specialist for liver transplantation consideration.⁴

References:

1. Chen Y, Fan Y, Guo DY, et al. Study on the relationship between hepatic fibrosis and epithelial-mesenchymal transition in intrahepatic cells. Biomed Pharmacother. 2020;129:110413. doi:10.1016/j.biopha.2020.110413
2. Tanwar S, Rhodes F, Srivastava A, Trembling PM, Rosenberg WM. Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J Gastroenterol. 2020;26(2):109-133. doi:10.3748/wjg.v26.i2.109
3. Khatun M, Ray RB. Mechanisms underlying hepatitis C virus-associated hepatic fibrosis. Cells. 2019;8(10):1249. doi:10.3390/cells8101249
4. AASLD and IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed October 15, 2020.
5. Asselah T, Bièche I, Sabbagh A, et al. Gene expression and hepatitis C virus infection. Gut. 2009;58(6):846-858. doi:10.1136/gut.2008.166348
6. Poynard T, Ratziu V, Benmanov Y, Di Martino V, Bedossa P, Opolon P. Fibrosis in patients with chronic hepatitis C: detection and significance. Semin Liver Dis. 2000;20(1):47-55. doi:10.1055/s-2000-9258
7. Hepatitis C Online. Evaluation and prognosis of patients with cirrhosis. https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/evaluation-prognosis-cirrhosis/core-concept/all. Updated May 31, 2018. Accessed October 15, 2020.
8. Yeom SK, Lee CH, Cha SH, Park CM. Prediction of liver cirrhosis, using diagnostic imaging tools. World J Hepatol. 2015;7(17):2069-2079. doi:10.4254/wjh.v7.i17.2069
9. Schuppan D and Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838-851. doi:10.1016/S0140-6736(08)60383-9
10. Centers for Disease Control and Prevention. Hepatitis C questions and answers for health professionals. Updated July 2019. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Accessed October 15, 2020.

 

 

Video 3: Identifying and managing patients without cirrhosis

Who is a patient without cirrhosis?

Patients without cirrhosis may have some liver damage, but have not progressed to more advanced liver disease known as cirrhosis.^1,2

No cirrhosis can include a range of liver fibrosis stages, from a normal, healthy liver (F0) to advanced fibrosis (F3).^1,2

You can find out more information about the stages of fibrosis in Video 2: Fibrosis and Cirrhosis of the Liver.

Patients without cirrhosis very rarely display any symptoms. However, patients with fibrosis stage F3 or higher are at increased risk of developing complications associated with advanced liver disease, and are recommended for frequent follow-up. Ongoing imaging surveillance for liver cancer and gastroesophageal varices is recommended for these patients.

The degree of hepatic fibrosis is key to determining the initial and follow-up management of patients.³

Several recommended non-invasive assessments of fibrosis are available.³

Liver biopsy is rarely required but may be considered if other causes of liver disease are suspected.³

Non-invasive tests include:

• Fibrosis-4 (FIB-4): A calculation for estimating the amount of scarring in the liver^4-6
• Aspartate aminotransferase to platelet ratio index (APRI): A calculation that uses laboratory data to estimate the likelihood of significant fibrosis or cirrhosis^4,6,7
• FibroSure^®: A biomarker test that assesses liver fibrosis—values correspond to METAVIR scoring from liver biopsy (F0-F4)^4,7-9
• FibroScan^®: Transient elastography that assesses liver stiffness^4,8-10

AASLD-IDSA HCV treatment guidelines for patients without cirrhosis

Treatment is recommended using the simplified treatment pathway for treatment-naïve patients without cirrhosis.³

Very little follow-up is required with the simplified treatment pathway.³

Referral to subspecialty care and consultation may be required for persons with HCV infection who have advanced fibrosis or cirrhosis.³

Patients with HCV infection and advanced fibrosis should be linked to a healthcare provider who is prepared to provide comprehensive management, including surveillance every 6 months for liver cancer utilizing ultrasound.³

FibroSure^® is a registered trademark of Laboratory Corporation of America Holdings.

FibroScan^® is a registered trademark of Echosens Company.

References:

1. Asselah T, Bièche I, Sabbagh A, et al. Gene expression and hepatitis C virus infection. Gut. 2009;58(6):846-858. doi:10.1136/gut.2008.166348
2. Poynard T, Ratziu V, Benmanov Y, Di Martino V, Bedossa P, Opolon P. Fibrosis in patients with chronic hepatitis C: detection and significance. Semin Liver Dis. 2000;20(1):47-55. doi:10.1055/s-2000-9258
3. AASLD and IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed October 15, 2020.
4. Ipsos Healthcare HCV Monitor, 2017, New York, NY: Ipsos in North America.
5. Sterling RK, Lissen E, Clumeck N, et al; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325. doi:10.1002/hep.21178
6. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Ann Intern Med. 2013;158(11):807-820. doi:10.7326/0003-4819-158-11-201306040-00005
7. Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53(3):726-736. doi:10.1002/hep.24105
8. Hepatitis C Online. Evaluation and staging of liver fibrosis. https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/evaluation-staging/core-concept/all. Updated May 31, 2018. Accessed October 15, 2020.
9. Patel K, Friedrich-Rust M, Lurie Y, et al. FibroSURE and FibroScan in relation to treatment response in chronic hepatitis C virus. World J Gastroenterol. 2011;17(41):4581-4589. doi:10.3748/wjg.v17.i41.4581
10. Castéra L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343-350. doi:10.1053/j.gastro.2004.11.018

 

 

Video 4: Identifying and managing patients with cirrhosis—compensated vs. decompensated liver disease

What is cirrhosis?

Cirrhosis is the end stage of chronic liver disease where there is extensive scarring of the liver caused by long-term liver damage.¹

Approximately 5% to 25% of people with chronic HCV infection will develop cirrhosis within 10-20 years.²

It can be classified as compensated or decompensated, depending on the extent of liver damage.

Understanding the severity of cirrhosis is important, as it has a significant impact on treatment, monitoring, and prognosis.

Measuring the severity of cirrhosis

A couple of methods are available to assess the severity of cirrhosis and predict clinical prognosis in patients with HCV infection.

• Child-Turcotte-Pugh Score (CTP) uses 5 clinical assessments to classify the severity of cirrhosis as compensated (CTPA) or decompensated (CTP B and C).^2-4
• Model for End-stage Liver Disease (MELD) assesses the severity of disease and estimates the survival probability using 4 clinical measures: serum bilirubin, international normalized ratio (INR), serum creatinine, and serum sodium.^5,6

What is compensated cirrhosis?

Compensated cirrhosis is the less severe classification, as the liver can perform most of its basic functions, despite the advanced stage of liver fibrosis.⁷

It is usually asymptomatic and the median survival is >12 years.¹

There is, however, an increased risk of developing liver cancer and hepatic decompensation.²

Compensated cirrhosis: AASLD-IDSA HCV treatment guidelines¹

Patients with advanced fibrosis and cirrhosis are recommended for specialist follow-up and screening for liver cancer.³

Patients with advanced fibrosis should be linked to a healthcare provider who is prepared to provide comprehensive management, including surveillance every 6 months for liver cancer utilizing ultrasound.³

What is decompensated cirrhosis?

Decompensated cirrhosis occurs when fibrosis is so advanced, the liver is no longer able to function normally.¹

Median survival time is ~2 years.²

There are a number of symptoms that may occur.

• Hepatic encephalopathy: Decline in brain function
• Jaundice: Yellowing of the eyes and skin
• Ascites: Abnormal build-up of fluid in the abdomen
• Variceal hemorrhage: Enlarged/swollen veins and bleeding in the abdomen and esophagus

Decompensated cirrhosis: AASLD-IDSA HCV treatment guidelines

Patients with HCV infection who have decompensated cirrhosis, including moderate or severe hepatic impairment (i.e., CTP Class B or C) should be referred to a medical practitioner with expertise in that condition, ideally in a liver transplant center.¹

Not all treatments approved by the FDA are approved for use in decompensated cirrhosis.¹

References:

1. US Department of Veterans Affairs. Viral hepatitis and liver disease. https://www.hepatitis.va.gov/index.asp. Updated October 1, 2020. Accessed October 15, 2020.
2. Centers for Disease Control and Prevention. Hepatitis C questions and answers for health professionals. https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Updated August 7, 2020. Accessed October 15, 2020.
3. AASLD and IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed October 15, 2020.
4. Poynard T, Ratziu V, Benmanov Y, Di Martino V, Bedossa P, Opolon P. Fibrosis in patients with chronic hepatitis C: detection and significance. Semin Liver Dis. 2000;20(1):47-55. doi:10.1055/s-2000-9258
5. Kamath PS, Kim WR; Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology. 2007;45(3):797-805. doi:10.1002/hep.21563
6. Hepatitis C Online. Model for dnd-stage liver disease (MELD) for ages 12 and older. https://www.hepatitisc.uw.edu/page/clinical-calculators/meld. Accessed October 15, 2020.
7. Hepatitis C Online. Evaluation and prognosis of patients with cirrhosis. https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/evaluation-prognosis-cirrhosis. Accessed October 15, 2020.

 

 

Video 5: Assessing liver damage caused by HCV infection: common laboratory tests

The damage caused by hepatitis C virus infection can be measured directly through fibrosis/cirrhosis assessments (see other modules), or through assessment of liver function using common laboratory tests.¹

Laboratory tests are recommended prior to treatment of patients with hepatitis C, and as part of monitoring for some patients.¹

The recommended laboratory tests consist of an assessment of the following:¹

• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Albumin
• Bilirubin
• Platelets
• Prothrombin time, international normalized ratio

AST and ALT

AST plays a role in amino acid metabolism.² ALT converts alanine to pyruvate needed for cellular energy.²

AST is found in the liver, heart, kidneys, muscles, and brain. ALT is found mostly in the liver.³

Measuring the levels of AST and ALT in blood serum can be a useful way to determine if there is liver damage.³

When there is no damage to the liver, there are low levels of ALT and AST in the blood. Damage to liver cells releases these enzymes from the liver and causes levels to increase in the blood.³

While increases of serum AST and ALT levels suggest damage to the liver, changes in these levels cannot be used to directly assess the degree of damage.³

Levels of AST and ALT can fluctuate between normal and elevated in patients with HCV infection.^3-6

Laboratory methodologies and analyses also vary, so AST/ALT data are typically reported as ranges or ratios.^3-6

The AST/ALT ratio is usually less than 1.0, but can increase as fibrosis advances. A ratio greater than 1.0 can suggest advanced fibrosis or cirrhosis.^3-6

Albumin

Albumin is the most common protein found in the blood and is synthesized by hepatocytes in the liver.⁷

The levels of albumin in the blood can give an idea of how well the liver is functioning.^3,5,8

A low level of albumin in the blood (hypoalbuminemia) can be a sign of advanced liver disease, such as cirrhosis, in which the liver is not able to synthesize the protein effectively.^5,8 Low levels of albumin can also be caused by kidney disease, malnutrition, or acute illness.

Very low levels of albumin can cause symptoms such as ascites and edema.⁹

The normal range for albumin is 3.4 to 5.4 g/dL. Values less than 3.4 g/dL can indicate cirrhosis.⁹

Bilirubin

Bilirubin is a component of bile needed for lipid digestion.⁵ It is formed as a result of the enzymatic breakdown of heme and is conjugated in the liver and secreted in bile.

There are 2 forms of bilirubin: indirect (or unconjugated or pre-hepatic) and direct (or conjugated).²

Indirect + direct = total bilirubin.

Increases in direct bilirubin can indicate:¹⁰

• Drug-induced liver injury
• Hepatocellular damage
• Intrahepatic cholestasis
• Extrahepatic cholestasis

Increases in indirect bilirubin levels in the plasma are observed in the later stages of a disease and can indicate:¹⁰

• Gilbert’s syndrome
• Crigler-Najjar syndrome, types I and II

Elevated levels of total bilirubin can result in patients presenting with jaundice, which can be indicative of advanced liver disease, such as cirrhosis.³

The normal range* of total bilirubin is 0.3 to 1.9 mg/dL. For direct bilirubin, it’s 0 to 0.3 mg/dL.

*Normal value ranges may vary slightly among different laboratories. Some laboratories use different measurements or may test different samples.

Platelets

Platelets are small fragments of cytoplasm that are vital for blood clotting.¹¹

A reduction in platelet count is a common complication seen with chronic liver disease.^11,12

Platelet count <150,000/µL is known as thrombocytopenia.^11,12

• Mild thrombocytopenia: 75,000/µL–150,000/µL
• Moderate thrombocytopenia: 50,000/µL–75,000/µL
• Severe thrombocytopenia: <50,000/µL

Thrombocytopenia affects approximately 6% of patients with HCV without cirrhosis and 70% of patients with cirrhosis.^11,12

Thrombocytopenia in patients with hepatitis C occurs because of a variety of reasons, including:

• The suppression of bone marrow production, which reduces platelet production
• Increased platelet destruction
• Reduced levels of thrombopoietin caused by chronic liver disease, which leads to decreased megakaryocyte proliferation
• Splenic sequestration of platelets from portal hypertension resulting in splenomegaly

Prothrombin time (international normalized ratio [INR])

• This is a measure of how long it takes for a patient’s blood to clot (in seconds).^14,15
• The main factors needed for blood clotting are produced in the liver.^14,15
• When the liver is damaged, it does not produce sufficient levels of these factors, causing an increase in the time it takes for the blood to clot.^14,15

These are the normal ranges of INR and prothrombin time:

	Normal Range
Not taking blood-thinning medications
Prothrombin time, seconds	11.0—13.5
INR	0.8—1.1
Taking blood-thinning medications
INR	2.0—3.0

In summary, there are a number of commonly used lab tests that assess liver function.

• Each test can vary in an individual over time and between labs, so it is important to include a panel of these tests.
• Liver tests are not diagnostic of a specific condition but indicate that there may be a problem with the liver.

AASLD-IDSA recommend carrying out these tests within 6 months prior to starting DAA therapy. Monitoring during and after treatment may vary depending on comorbidities and cirrhosis status.¹⁶

See the pre-treatment, on-treatment, and posttreatment monitoring guides and the AASLD guidelines for more details.

Laboratory lab test codes for hepatic function panel:^17,18

CPT code: 80076, LabCorp: 322755, Quest Diagnostics: 10256

References:

1. Ghany MG, Morgan TR; AASLD-IDSA Hepatitis C Guidance Panel. Hepatitis C guidance 2019 update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology. 2020;71(2):686-721. doi:10.1002/hep.31060. PMID: 31816111
2. Mayo Clinic. Liver function tests. https://www.mayoclinic.org/tests-procedures/liver-function-tests/about/pac-20394595. Updated July 13, 2019. Accessed October 15, 2020.
3. US Department of Veterans Affairs: Viral hepatitis and liver disease, tests of liver function. https://www.hepatitis.va.gov/hcv/patient/diagnosis/labtests-liver-tests.asp. Accessed October 15, 2020.
4. Neuschwander-Tetri BA, Ünalp A, Creer MH. Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels. Arch Intern Med. 2008;168(6):663-666. doi:10.1001/archinternmed.2007.131
5. Kasarala G, Tillmann H. Standard liver tests. Clin Liver Dis (Hoboken). 2016;8(1):13-18. doi:10.1002/cld.562
6. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Ann Intern Med. 2013;158(11):807-820. doi:10.7326/0003-4819-158-11-201306040-00005
7. Lab Tests Online UK. Albumin. https://labtestsonline.org.uk/tests/albumin. Updated April 24, 2019. Accessed October 15, 2020.
8. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Ann Intern Med. 2013;158(11):807-820. doi:10.7326/0003-4819-158-11-201306040-00005
9. University of Rochester Medical Center Health Encyclopedia. Albumin (Blood). https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=albumin_blood#:~:text=A%20normal%20albumin%20range%20is,surgery%20or%20a%20heart%20attack. Accessed October 15, 2020.
10. The Association for Clinical Biochemistry and Laboratory Medicine. Bilirubin - Dr William Marshall. https://www.acb.org.uk/our-resources/science-knowledge-hub/analyte-monographs.html. Accessed October 15, 2020.
11. Garraud O, Cognasse F. Are platelets cells? And if yes, are they immune cells? Front Immunol. 2015;6:70. doi:10.3389/fimmu.2015.00070
12. Afdhal N, McHutchinson J, Brown R, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008;48(6):1000-1007. doi:10.1016/j.jhep.2008.03.009
13. Moore A. Thrombocytopenia in cirrhosis: a review of pathophysiology and management options. Clin Liver Dis (Hoboken). 2019;14(5):183-186. doi:10.1002/cld.860
14. NIH U.S. National Library of Medicine MedlinePlus website. Prothrombin time (PT). https://www.nlm.nih.gov/medlineplus/ency/article/003652.htm. Updated October 8, 2020. Accessed October 15, 2020.
15. University of Rochester Medical Center Health Encyclopedia. International normalized ratio. https://www.urmc.rochester.edu/encyclopedia/
content.aspx?contenttypeid=167&contentid=international_normalized_ratio. Accessed October 15, 2020.
16. AASLD and IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidlines.org. Accessed October 15, 2020.
17. LabCorp. Hepatic function panel (7). https://www.labcorp.com/tests/322755/hepatic-function-panel-7. Updated September 22, 2020. Accessed October 15, 2020.
18. Quest Diagnostics™. Hepatic function panel. https://testdirectory.questdiagnostics.com/test/test-detail/10256/?cc=MASTER. Accessed October 15, 2020.

 

 

Video 6: How can liver damage be assessed to identify appropriate patients for simplified HCV treatment?

Assessing fibrosis and cirrhosis

Liver damage, resulting from HCV infection (or other causes), can be assessed using a number of different methods.

The following invasive and non-invasive methods may be used to determine the extent of fibrosis and/or cirrhosis.

Overview: invasive tests

Liver biopsy is one invasive test that uses the METAVIR scoring system to assess the extent of inflammation and fibrosis in the liver.¹

Four non-invasive methods are also commonly used to assess liver damage:

• Fibrosis-4 (FIB-4): A calculation for estimating the amount of scarring in the liver^2-4
• FibroSure^®: A biomarker test that assesses liver fibrosis—values correspond to METAVIR scoring from liver biopsy (F0 ̶ F4)^2,5-7
• Aspartate aminotransferase to platelet ratio index (APRI): A calculation that uses laboratory data to estimate the likelihood of significant fibrosis or cirrhosis^2,4,5
• FibroScan^®: Transient elastography assesses liver stiffness^2,6-8

Liver biopsy and METAVIR

METAVIR assesses fibrosis stage via a liver biopsy¹ (see video 2.0 for more detail on fibrosis staging).

• While liver biopsy is still the gold standard to evaluate liver damage, it is rarely required unless causes other than hepatitis C are suspected⁹
• Liver biopsy is usually carried out by a specialist

AASLD and IDSA recommend the use of a number of non-invasive tests to determine the level of liver fibrosis.

Non-invasive tests for liver fibrosis

FIB-4

Fibrosis-4 (FIB-4) is one of several non-invasive tests that AASLD and IDSA recommend to determine the stage of liver fibrosis.

• It is a quantitative method to estimate the risk of advanced liver disease; calculated using age, serum levels of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and platelet count^2-4
• Calculators for FIB-4 are available online.
• A score of >3.25 suggests high likelihood of advanced liver disease (F3 ̶ 4)

APRI

AST to platelet ratio index (APRI) is a quantitative method to estimate the risk of fibrosis and cirrhosis using AST and platelet count.

• It is a validated method for predicting progression of liver disease due to HCV infection. The very low and very high values mean APRI can avoid further invasive testing in a substantial proportion of patients.^2,4,5
• Calculators for APRI are available online.
• A score of <1 suggests low likelihood of cirrhosis.

FibroSure^®

FibroSure is a commercially available test that provides a quantitative method to estimate the level of liver scarring using six biochemical serum markers, age, and gender.^2,5-7

• Scores range from 0.00 ̶ 1.00.
• A score of greater than 0.74 indicates cirrhosis.

CPT code: 81593 | Quest Diagnostics™ code: 92688 | LabCorp code: 550123

FibroScan^®

FibroScan is a non-invasive device that measures liver stiffness using transient elastography.^2,6-8

It requires ultrasound evaluation (the more rapid the wave, the stiffer the liver).^2,6-8

The advantages of FibroScan are:¹⁰

• It is not invasive
• It can be performed at point of care
• It is very quick and the results are instant
• It does not require sedation, and there is no pain¹⁰

The limitations are:

• It cannot be used in patients with ascites, those who are morbidly obese, or those with large amounts of chest wall fat.¹⁰

FibroScan tests are largely performed by hepatologists and gastroenterologists.¹¹

A score of greater than 12.5 kPa indicates cirrhosis.

Ruling out cirrhosis: Negative predictive value of non-invasive liver fibrosis tests

• APRI ≤1 is 95% predictive of not having cirrhosis⁴
• Fib-4 <3.25 is 92% predictive of not having cirrhosis⁴
• FibroSure <0.56 is 97% predictive of not having cirrhosis⁴
• FibroScan <12.5 is 98% predictive of not having cirrhosis¹²

APRI, AST to Platelet Ratio Index; FIB-4, Fibrosis-4.

Using the published sensitivities and specificities for each test, in a population with a cirrhosis prevalence estimate of 15%.¹

Significance of the test results

Pre-treatment assessments, such as the non-invasive methods described in this module, can help evaluate patients eligible for simplified treatment.⁹

Patients with chronic hepatitis C (any genotype) who do not have cirrhosis or have compensated cirrhosis and have not previously received treatment for hepatitis C are eligible for simplified treatment.⁹

All persons with an active HCV infection should be linked to a healthcare provider who is prepared to provide comprehensive management.⁹ For more details: Refer to the pre-treatment assessment guide and the AASLD-IDSA guidelines.

FibroSure^® is a registered trademark of Laboratory Corporation of America Holdings.

FibroScan^® is a registered trademark of Echosens Company.

References:

1. Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598-607. doi:10.1016/j.jhep.2007.07.006
2. Ipsos Healthcare HCV Monitor, 2017, New York, NY: Ipsos in North America.
3. Sterling RK, Lissen E, Clumeck N, et al; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325. doi:10.1002/hep.21178
4. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Ann Intern Med. 2013;158(11):807-820. doi:10.7326/0003-4819-158-11-201306040-00005
5. Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53(3):726-736. doi:10.1002/hep.24105
6. Hepatitis Online. Evaluation and staging of liver fibrosis. https://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/evaluation-staging/core-concept/all. Updated May 31, 2018. Accessed October 15, 2020.
7. Patel K, Friedrich-Rust M, Lurie Y, et al. FibroSURE and FibroScan in relation to treatment response in chronic hepatitis C virus. World J Gastroenterol. 2011;17(41):4581-4589. doi:10.3748/wjg.v17.i41.4581
8. Castéra L, Vergniol J Foucher J, et al. Prospective comparison of transient elastography, fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343-350. doi:10.1053/j.gastro.2004.11.018
9. AASLD and IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed October 15, 2020.
10. Afdhal N. Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol (N Y). 2012;8(9):605-607.
11. Top Doctors. FibroScan. https://www.topdoctors.co.uk/medical-dictionary/fibroscan#:~:text=Fibroscan%20tests%20are%20largely%20performed%20by%20hepatologists%20and%20gastroenterologists. Accessed October 15, 2020.
12. Cross TJ, Calvaruso V, Maimone S, et al. Prospective comparison of Fibroscan, King’s score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection. J Viral Hepat. 2010;17(8):546-554. doi:10.1111/j.1365-2893.2009.01210.x

 

 

Video 7: Overview of HCV Care in PWID

The epidemiology of HCV infection is changing. Historically, the burden of HCV infection was in patients born between 1945 and 1965. But this has now shifted to a younger population- patients born between 1981 and 1996. Following a decade of increases in acute HCV infections, primarily in young adults, the rates of new chronic infections are now equal among baby boomers and millennials in the United States. This shift in patient demographics has led to many guidelines now recommending universal screening for all adults. 

The main route of hepatitis C transmission in the United States in Europe is injection drug use, which accounted for 72 percent of all new HIV infections in the U.S. in 2018. 

In the U.S., the high rates of HCV and people who inject drugs is in part attributable to the opioid epidemic. This has potentially been made worse by decreased access to treatment and a surge in opioid misuse during the COVID 19 pandemic. In addition to the change in primary age groups, there has also been a shift from treatment experienced patients to treatment naive patients who now make up 98 percent of the HCV population in the United States. 
 
The use of direct acting antiviral treatment for HCV infection has shown similar results in terms of efficacy and safety, and people who inject drugs and those on opioid substitution therapy compared with the general population. However, reaching these populations is often harder, creating a barrier to treatment. Increasing the pool of providers able to treat HCV infection could increase diagnosis and treatment rates. Addiction specialist could be key to engaging people who inject drugs in every aspect of the care cascade, including post cure surveillance and education about reinfection, which is vital to achieve HCV elimination. 

 

 

Video 8: Awareness of HCV within the PWID Community

Speaker1: Tell us how you acquired it, and let's dive into that story a little bit. 
 
Speaker2: Can I be frank about it? 

Speaker1: Absolutely. 

Speaker 2:Ok, so being an IV drug user has its downfalls, obviously to it. For the longest time, I would never use a dirty needle, never considered anything of the sort, always even told myself I would never do it. But when that desperation kicks in, or you're just in that moment. You break those rules that you kind of once set for yourself, and it leads to a path, and in my own head, I remember I had had a lot of friends or known people who had had it, and I was always sure that would never happen to me. But I can recall only two times if ever having shared a needle, and that's how fast it happened. That's all it took was one of those two times. 

 
Speaker1: How old were you when you started using drugs? 
 
Speaker2: Started using or IV? 

Speaker1: Both. 

Speaker2: Started using drugs at 19. IV, at 21 or 22. 
 
Speaker1: And how did the whole thing begin? Do you recall any specific triggers that- 
 
Speaker2: Of how these actions started? 

Speaker1:Yeah. 

Speaker2: Yeah. I just got my first apartment. I was a young kid. I was 18 or 19, like I said and I was sleeping on an air mattress in my apartment because I was so broke. That's all I could afford. But I was really happy with it and I'd never tried drugs or anything before this. I was sleeping on an air mattress and I was also working at a lumber yard at the time. My back was really hurting and I called in to work for a couple of days. And this is my first time as an adult, maybe experiencing some kind of like real pain. I went and bought a new bed. Like, right then and there on my days off, I went and bought a new bed because I thought that was the issue. It didn't go away, so I end up going to the emergency room and this was back when opiates or opioids were prescribed a little more frivolously. And I got my first prescription for painkillers. 
 
Speaker1: Where was your head at when they told you that you were positive? What were your first thoughts? 

Speaker2: I actually cried. This was my first time where I really it's hard to explain, really set out to get clean and I was going to do it no matter what it took. I was in detox and they like it brought me the news and there was like kind of a case worker that had brought me the news. And I cried because then I realized I didn't know that much about Hep C because it worried me. I didn't know, you know what treatment looks like. Is there treatment or what life would look like after that? I just knew basically how it was contracted, but not what the future for me would look like after that.  

Speaker1: So you're worried about treatment and the whole process. Could you get access to treatment, things like that? 
 
Speaker2: Yeah. And what it would do to my body? Yeah, really. Just what the future would look like for that. 
 
Speaker1: What did you know about treatment, were you? Were you afraid of it? 
 
Speaker3: Yeah, yeah. The only the only thing I had ever heard was that treatment can make you sick. I talk to people that were older, that had gone through treatment, and they had discussed, you know, how ill they became after they took the medicine. And that kind of pushed me away because I never wanted to feel sick. That was the biggest thing for me of trying to get clean because I could never go long enough without getting sick to get clean. So anything that surrounded me, feeling flu like symptoms or anything like that, I kind of shied away from so... 
 
Speaker1: Right, because a lot of those old side effects mimicked right side well, mimic withdrawal symptoms for opiates. And yeah, that's a that's a common refrain that we also hear from patients. 

 

 

Video 9: Stigma and HCV: A Barrier to Seeking Help

Speaker1: Talk to me a little bit about stigma. This is still a huge thing around Hep C and a lot of it's driven, in my opinion, on how Hep C gets acquired and it really the root of it lies in the addiction. But I'm interested in your thoughts about this aspect, 
 
Speaker2: The stigma of the disease or the stigma of addiction? 
 
Speaker1: All of it. 
 
Speaker2: A lot of the reason I never found help. And still, sometimes I don't go to doctors or ask anybody for help is because of that stigma. Just after a few years of like kind of proving myself, I feel like that stigma has been lifted just enough to operate. That stigma can really hold you back. And people that get into this line of work, even in your line of work, I feel like, you know, not you guys, but they have that stigma of there's no hope for this person or we turn out so many of these people or we see so many people come and go and you're a flight risk. You don't want help. And, you know, people like me had proved that time and time and time again. And really that stigma is really discouraging. And with addiction comes that lack of wanting to ask for help. And then when it comes to asking for help, you don't want to go ask for help because of the way you talk to the way you're treated, the way you're dismissed, the way you're not a credible person from the get go. When you tell somebody I'm an addict, especially a doctor previously, is how I had felt. And that stigma is probably the probably the biggest issue, was one of the biggest issues for me, to go get real genuine help.

Speaker3: So I didn't really want to share my diagnosis with a lot of people because I was afraid that people wouldn't want to be around me and use around me at the time when I was still getting high. So I kind of kept it hush hush. But like I said, I did take the precautions of getting, you know, needles from the needle exchange so that I, if somebody asked to use my needle, I could just give them a brand new needle. But as far as the stigma goes, you know, even today, sitting here with three over three years clean, the stigma is still there. I share openly about my past and you know what I'm doing now in my in what I'm going to continue to do in my future because I feel like if more people share about the things that they've gone through, the stigma will not be there as much. But there's always going to be people that judge you. 
 
Speaker1: Yeah. And I think especially around Hep C, a lot of it has to do with how you acquire it. And that's why that stigma still persists as far as the virus now. It really kind of points back toward the addiction part of it.

 

 

Video 10: Stigma and HCV: Treatment Without Discrimination

Speaker1: And how did you feel when you first came into the clinic to get evaluated for all this stuff with us? 
 
Speaker2: My first time  into the clinic, I had met you once already in rehab, they wouldn't let me meet with you because we were kind of locked away. I loved it, I loved it ever since. There's really just like a judgment free kind of feeling as that might sound kind of cheesy, but like there really is that judgment free feeling, especially in like that corner of your building where just the people that work there in the atmosphere and you were the first person I had ever met that like talk to me like a human. I felt like when I came to them saying that I have a problem. 
 
Speaker1: We hear a lot from patients that when they go to new providers, you know that if they've been referred somewhere to a specialty clinic or something like that, that a lot of times they feel that they're not seen. That the stigma of their medical history kind of follows them. Did you ever face that with any of your any of your treatment centers? 
 
Speaker3: I did at one point, you know, I kind of just felt like a number when I came to your office to get treatment, though I definitely felt comfortable and at home. And I always say that because everybody greeted me and they just treated me like I was, you know, an equal, a peer. So it wasn't really until then that I actually felt that way, at every other outpatient facility I've ever gone to or any clinic. You know, I think a lot of times people look down on us as addicts or, as, you know, being treated for Hep C. So I will say that that experience was my first experience actually feeling, you know, like I was a part of...

Speaker1: Safe. 
 
Speaker3: Yeah.

 

 

Video 11: The Impact of Cure Beyond Clinical Outcomes

Speaker1: So you get through and you find out that you're cured. You hear the words, you're cured. How do you feel? 
 
Speaker2: It was awesome. I was really excited and I got to come and ring the bell. 
 
Speaker1: For the people who don't know, we have a we have a bell. And when patients get cured, they sign. They graffiti the walls of the clinic and we have a cow bell that they ring. And so Lindsey obviously signed and rang the bell and celebrated. It's very emotional when whenever somebody does that, it's it's emotional for all of us, right? Did you feel like you maybe turned a page on something by getting rid of this? 
 
Speaker2: Yes, definitely. You know, because like my biggest concern was not giving it to anybody else and the fact that, you know, I am a mom, I have two children and I did acquire custody back of them after getting clean. So, you know, I was just nervous of giving it to them. You know, I'm always cleaning everything, you know, they take showers after me and stuff like that. So it just it was very yeah, it was anxiety ridden. So after ringing the bell and knowing that I was cured, it was like, OK, this is, I can move on to the next chapter in my life. I don't have to worry about this at least and push forward. 
 
Speaker1: Did you feel hopeful when it was over? 
 
Speaker2: Definitely. Yeah. 

Speaker1: Empowered? 

Speaker2: Yes, definitely. 

Speaker1: So you've come an extraordinarily long way in your life, and we've heard now from a young age starting with drugs to where you are now. Tell us, tell us about that. Tell us what you're doing now. 
 
Speaker2: So after I was clean for a little over a year, I decided that I wanted to work in the field and help other people with their addiction. So I became a peer advocate and I worked at a couple of different agencies, helping addicts get through their tough times and trying to help them on their journey to stay clean. I went from one agency to the next agency and I'm actually about to start working for a different agency. So I've just been basically a resource broker for people with addictions, so I link them with different services to help them throughout their recovery, 
 
Speaker1: Helping people on that journey from that you've gone through that you've done. It's a it's a very powerful story, from how you started to where you are. And it's really it's a story of redemption. I think. You viewed sort of getting the Hep C dealt with is the first step in getting a handle on the addiction. 
 
Speaker3: One hundred percent. Yeah, getting your health dealt with in general. And it's I mean, Hep C obviously was the forefront of my health problems at the time, aside from addiction. What point would there be to move forward, know if I had some other kind of monkey on my back that felt like it was dragging me down physically? 
 
Speaker1: I think that's important for a lot of other patients to hear too, because, you know, in the old days, you had to have a period of sobriety for six months before you were eligible for treatment. And I think yours is a great example where, you know this paradigm is completely changed. That's no longer the case. So active substance use is no longer a barrier to treatment for Hep C, and I think your story is an example how quickly getting the Hep C treated like, you said can serve as a first step to actually deal with the addiction. 

Speaker3: Absolutely. 

 

 

Video 12: Advice for Other Patients with HCV

Speaker1: Imagine you're sitting with a kid just like you today, somebody who's in the position that you were in. What's the single most important piece of advice you would give them? 
 
Speaker2: Get real help. Sorry, I'm going to stumble over this. There's not a lot of advice you can give because of that thing, people say you're not ready to get help until you're like actually willing to get help or however that statement goes, that's like really true. So like, every time can count. So just like keep the even if those attempts at getting your life together or getting healthier, you know, getting over your addiction, fail like that fourth, fifth that sixth time, literally just pick your head up every time. You won't get help until you're ready. You won't like really want it. There's something that clicks in your brain that's really just had enough that you're willing to walk 10 miles across town in the snow to go get help. Just keep your head up, I know that's kind of cliche, but really just keep your head up. That's what I did for many years, for about 10 years, just not giving up. As cheesy as that might sound, that's really the only way to get through it. And once you experience that feeling of such desperate need for help, you'll know it and something in your mind is different. It's like I just had my daughter. It's like experiencing that parent love. You know, when a when a baby is born or something, you'll know the difference in your mind and really just try to run with that and work your butt off. I tried a lot of times and no one ever thought I would make it out of it. But you just literally have to keep going. 
 
Speaker1: I'm proud of you, man. If you're sitting with someone who's newly diagnosed with Hep C, who's currently in the situation that you were in. What's the single most important piece of advice that you give that individual? 
 
Speaker3: Just hold on. Because, you know, I always say like hope, hold on. Pain ends because no matter what, you can get through it. 
 
Speaker1: Awesome. That's great. Thank you, Lindsey.

 

 

Video 13: HCV Care for PWID – Anne Øvrehus

Hi, I'm Anne. I'm an infectious disease physician from Denmark, and I work here a couple of times a month in our local OST clinic. It's a service where we basically take the hospital outpatient care into the OST clinic to provide care and treatment for people who inject drugs that are infected with hepatitis C.

I think all of us who work here, I'm not the only physician providing the service at this center, agree on that this is a very satisfying part of our job, and I think it's because we feel that what we do really make sense and that we provide a service that's of use to people. And we can see when people get tested and go on treatment and get cured, that each step is a success in a life where successes are not that frequent, and a lot of them have gone through a transformation period in that time because they accomplished something. And I think this is a clinic where I get the most smiles and the most hugs, and I think it's totally undeserved because I don't do anything very hard or very special, but it really does bring something to people, and I think that's very satisfying for the physician to be able to be part of that.

 

 

Video 14: HCV Outreach in Addiction Medicine – Lorna Harrison

My name is Lorna Harrison. I'm a clinical nurse specialist in hepatology. I'm based at St. Mary's Hospital in Paddington, London. My role is mainly within community outreach.

So I always had an interest in the treatment side of hepatitis C, but mainly with patients from addiction, background and mental health.

Most of those patients weren't accessing treatment. So once I started within my role at St Mary's, the idea was that the patients would attend the hospital. But I found they weren't attending their appointments. And because I already had the link with the drug and alcohol services, I was able to go into those services, offer training to the staff, to the patients and find out why they weren't attending. And then we realized there were lots of stigmas, lots of barriers preventing them from coming to the appointments.

In order to eliminate hepatitis C, we have to be more proactive and more inventive in our approach. So most patients do not want to come to the hospital, so we offer them appointments either at the drug and alcohol service, via home visits or at the homeless hostel. 

I think we can improve the situation greatly, having more nurses or health professionals on board working within the community. But it's to have someone with that flexibility because having rigid appointments and expecting people to be there at the exact time isn't going to work. So we need to be flexible and work with the individual and with the community services.

But I find more satisfaction from coming into the community, either going into the drug and alcohol services, into the hostel or into patients home, offering them treatment on their grounds, on their terms. It's a lot more satisfying because you can see the benefits and the appreciation.

Seeing patients at the hostel. It's a captive audience because I'm bringing the medication to them and bringing the treatment to them. They're more likely to engage. They're more likely to attend because I'm meeting them more than halfway.