I. What every physician needs to know.
Hepatitis C virus (HCV), previously called “non-A, non-B hepatitis” is a single stranded RNA virus of the Flaviviradae family that was first described in 1989. HCV is only known to infect humans and chimps, though it can also be grown in cell culture (replicon system).
Variations in the hepatitis C virus have been classified into six genotypes (1 through 6) based on their genetic heterogeneity. The distribution of each genotype varies in different regions of the world and continues to change with immigration patterns. In the United States, genotype 1 is the most common, accounting for nearly 75% of HCV infections, followed by genotypes 2 and 3 in 20% collectively.
Hepatitis C can cause both acute and chronic hepatitis. Acute HCV infection is typically asymptomatic and only very rarely leads to acute liver failure. An estimated 15-25% of infected people are able to spontaneously clear the virus without antiviral treatment. The remaining people will go on to develop chronic hepatitis C infection. In patients with chronic infection, about 5-20% will develop cirrhosis after 2-3 decades. Furthermore, those with cirrhosis are at an increased risk of developing hepatocellular carcinoma, estimated at 1-6% per year. HCV is a common cause of chronic liver disease and the most frequent indication for liver transplantation in the United States. Many HCV infections occurred between 1960 and 1990 and this cohort of patients is now at an age when cirrhosis has developed. The prevalence of HCV cirrhosis is expected to substantially decrease as this cohort dies from their cirrhosis, receives liver transplantation or is cured with the new highly effective antiviral therapies.
Mode of transmission
HCV is primarily transmitted by percutaneous exposure (i.e., blood transfusion, injection drug use, needle stick injuries, intranasal cocaine use, and occupation exposures) and less commonly by sexual contact or at the time of delivery from mother to child. The risk of transmission from a single accidental needle stick injury is about 0.3%. The risk of transmission during childbirth is less than 5% but is increased in mothers who are HIV- positive.
Who should be tested?
All people born between 1945 and 1965
People with high risk behaviors
Current of past injection drug use
Intranasal drug use
People with possible exposures
Long term hemodialysis
Tattoo placement in an unregulated setting
Healthcare, emergency medical, and public safety workers after exposure to HCV-infected blood
Children of HCV-infected women
Recipients of blood transfusions or organ transplants prior to 1992
Recipients of clotting factors prior to 1987
History of incarceration
People with conditions associated with increased risk of infection
Unexplained chronic liver disease
Unexplained ALT elevation
II. Diagnostic Confirmation: Are you sure your patient has hepatitis C?
Most people are asymptomatic or have only nonspecific symptoms (e.g., fatigue and malaise) in the acute phase after initial infection. Diagnosis of acute hepatitis C is therefore rarely made. Chronic hepatitis C may be identified at the time of workup for causes of aminotransferase elevations; however, the majority of people with chronic HCV infection remain asymptomatic until the disease progresses to advanced stages of fibrosis or cirrhosis.
Presence of anti-HCV antibodies (HCV Ab) confirms prior infection with HCV. To determine if a patient has current HCV infection, HCV RNA is measured. A patient with detectable serum HCV RNA has chronic HCV infection. A patient with a positive HCV Ab but undetectable HCV RNA was previously exposed to HCV but either spontaneously cleared the infection or was cured by prior treatment (i.e., this patient does not have chronic HCV infection if the RNA is negative). During the early phases of an acute infection, patients may not have developed HCV antibodies; therefore, if acute HCV infection is suspected, HCV RNA should be checked despite a negative HCV Ab result. Additionally, patients who are immunocompromised (e.g., chronic hemodialysis, cancer chemotherapy) may have negative antibody testing but active infection as indicated by a positive HCV RNA test. In such patients with aminotransferase elevations that remain unexplained after typical causes are excluded, HCV infection should be fully excluded by RNA testing.
B. History Part 2: Prevalence:
An estimated 170 million people have chronic HCV infection globally. In the United States, an estimated 2.7-3.9 million people are chronically infected with hepatitis C. The overall incidence rate in 2014 was estimated to be 0.7 cases per 100,000 people although this may be underestimated as there remain patients who are undetected. The incidence of acute HCV infection in the United States had declined dramatically after the initiation of routine blood product screening for HCV in 1990 followed by improved testing in 1992. The majority of new HCV infections in the United States are due to injection drug use.
C. History Part 3: Competing diagnoses that can mimic hepatitis C.
Both acute and chronic hepatitis C infection are indistinguishable from other causes of hepatitis based on clinical features alone. Confirmation with HCV testing is required to make a definitive diagnosis.
The main alternative diagnoses to consider in setting of acute hepatitis (i.e. ALT or AST > 500 U/L) include any of the other forms of viral hepatitis (HAV, HBV, EBV, CMV, HSV), alcoholic liver disease, autoimmune hepatitis, ischemic hepatitis or other vascular compromise, drug-induced liver injury, or acute biliary obstruction.
In chronic hepatitis (ALT typically ranges from normal to 500 U/L), alternative diagnoses to consider include chronic hepatitis B, autoimmune diseases (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis), metabolic disorders (nonalcoholic steatohepatitis, Wilson’s disease, alpha-1 antitrypsin deficiency), drug-induced liver injury (including over-the-counter medications, herbal medications, weight loss supplements, body building supplements) and alcoholic liver disease.
D. Physical Examination Findings.
Acute hepatitis C
Acute hepatitis C is typically asymptomatic. Up to 20-30% of patients may develop clinical symptoms including jaundice, dark urine, pale stool, arthralgias, fatigue, abdominal pain, nausea, vomiting, and decreased appetite. If patients do have symptoms, they typically present 4-12 weeks after exposure with complete resolution by 24 weeks.
Chronic hepatitis C
Chronic hepatitis C infection is usually asymptomatic though some may have mild nonspecific symptoms such as fatigue, myalgia, arthralgia, weakness or weight loss. Up to 20% of patients will go on to develop advanced fibrosis or cirrhosis at which time they may present with signs or symptoms including ascites, hepatic encephalopathy, jaundice, easy bleeding or bruising, spider angiomata, palmar erythema, or gynecomastia.
Extrahepatic manifestations of chronic HCV infection occur in up to 40% of patients, including:
Mixed cryoglobulinemia: palpable purpura, arthralgias, renal dysfunction i.e., membranoproliferative glomerulonephritis, vasculitis, hypocomplementemia
Autoimmune disorders, i.e., Sjogren’s syndrome, rheumatoid arthritis, lupus, thyroid disease – note that up to 65% of patients may have autoantibodies suggestive of autoimmune disease but without clinical significance
Porphyria cutanea tarda: photosensitivity, blistering skin lesions, skin fragility, hypo- and hyperpigmentation, especially on sun exposed skin such as the dorsum of the hands
Leukocytoclastic vasculitis: palpable purpura, petechiae
Lichen planus: flat, violaceous, pruritic papules
Necrolytic acral erythema: pruritic, psoriasis-like rash
E. What diagnostic tests should be performed?
HCV RNA PCR
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Anti-HCV is typically detectable in serum 4-10 weeks after exposure. HCV RNA is detectable in serum as early as 2-3 weeks after exposure.
HCV antibody is the first screening test to order in a patient with suspected infection based on risk factors or unexplained aminotransferase elevations. If the antibody is not detected but an acute infection is suspected, then HCV RNA is checked since the antibody takes longer to become detectable in the serum or it may never become detectable in immunocompromised patients.
If HCV RNA is detectable, the patient has either acute or chronic HCV infection. The clinical setting usually differentiates between these two states. In someone with remote risk factors such as IV drug use years earlier and no recent risk factors, the diagnosis is highly likely to be chronic HCV infection. In someone with both remote and recent risk factors such as ongoing IV drug use, a distinction between acute and chronic infection cannot be made unless older records are available that provide information on the patient’s prior HCV status.
A positive HCV antibody with undetectable HCV RNA indicates prior infection with spontaneous clearance of the virus. These patients do not have chronic HCV. In addition, after successful treatment with antiviral therapy, patients will continue to have a positive HCV antibody with undetectable HCV RNA lifelong. If a patient reports prior effective therapy for HCV infection, there is no need to check their antibody status as they will be positive. HCV RNA can be rechecked in such patients if they have risk factors since being cured such as resumption of IV drug use or if there is uncertainty about their history of being cured.
Once a patient has been found to be HCV RNA positive, there is no value in repeating RNA testing until treatment is to be initiated. There is no significant correlation between serum HCV RNA levels and disease activity or rate of progression. Patients attuned to HIV management are sometimes mistaken in believing that their HCV RNA levels should be monitored over time. There is no need for doing this unless they are being monitored during treatment.
Genotyping is important for appropriate management and should be performed if HCV RNA is detected. Treatment regimen is usually determined by the genotype, but this testing and these decisions are usually made in the outpatient setting.
In acute HCV infection, ALT and AST elevations can be seen as high as 1000s with peak levels at 6-12 weeks. In chronic HCV infection, aminotransferase levels are variable and may be normal in about 25% of the cases. There is no correlation with the degree of aminotransferase elevation and disease severity or prognosis. ALT elevations greater than 500 IU/ml are unusual with chronic hepatitis C and raise the possibility of another coexisting process such as autoimmune hepatitis or drug toxicity.
Elevated bilirubin or low albumin levels may suggest progression to cirrhosis.
Advanced fibrosis, or cirrhosis, should be considered in patients with unexplained coagulopathy (elevated INR) or thrombocytopenia (low platelets). This can be further assessed with imaging, elastography or serum fibrosis markers.
Suspicion for extrahepatic manifestations may require additional laboratory testing as appropriate. For instance, cryoglobulinemia can be further assessed by measuring cryoglobulins, C3, C4, CH50, and RF.
Additionally, as with other chronic liver diseases, alternative or additional causes should be ruled out with diagnostic laboratory testing.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Imaging studies are not required for the diagnosis of acute or chronic hepatitis C. However, imaging should be considered in patients with chronic infection who have clinical signs or symptoms suggestive of advanced fibrosis who lack recent imaging of the abdomen. In general, ultrasound is the preferred method of initial imaging, followed by CT or MRI if ultrasound imaging is inadequate or further characterization of liver lesions is needed.
Liver biopsy does not contribute to making the diagnosis of hepatitis C infection. Historically, liver biopsies were obtained fairly routinely to determine the stage of liver fibrosis and grade of inflammation; however newer noninvasive tests and well-tolerated antiviral treatments are now available that reduce the need for liver biopsies.
Non-invasive tests of liver fibrosis
A number of serum biomarker panels for predicting degree of liver fibrosis are now commercially available. These panels include markers of matrix deposition (hyaluronic acid, laminins, procollagen I and III peptides), matrix degradation (matrix metalloproteins, tissue inhibitors of MMPs), and cytokines (transforming growth factor beta and alpha, platelet derive growth factors). The most commonly available panels available include HepaScore, FibroIndex, FibroSure, and Fibrotest, and FIB-4 index.
Transient elastography (Fibroscan), acoustic radiation force impulse imaging (ARFI) and magnetic resonance elastography (MRE) are now available as noninvasive methods to stage fibrosis in the liver. These are not yet widely available and may require referral to a tertiary care center. The greatest advantage include their noninvasive nature, sample size 100 times greater than a standard liver biopsy (1:50,000) and relative ease. Some can be performed easily and quickly during an office visit. Fibroscan and ARFI can identify advanced fibrosis (stage 3-4) but cannot reliably identify lesser degrees of fibrosis.
III. Default Management.
Note: With the advent of new direct acting antiviral agents, treatment of hepatitis C is very rapidly changing and is being constantly updated as new medications are being made available. For the most up to date information, readers are advised to refer to the practice guidelines jointly from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) available at www.hcvguidelines.org.
Acute hepatitis C
Since up to 25% of acute hepatitis C infections may be spontaneously cleared, treatment is not advised until 6 months after exposure if the history suggests recent risk factors. At that time, if HCV RNA remains detectable in the serum, then antiviral therapies should be considered.
Chronic hepatitis C
With the advent of the new direct-acting antiviral agents (DAAs), treatments are now available for all genotypes that no longer require use of interferon. The antiviral agents and length of treatment are determined by the viral genotype, presence of absence of cirrhosis, prior treatment failure, and to some extent, insurance approval. Since there are few side effects with these new medications, treatment is recommended nearly universally for patients with chronic hepatitis C who have the potential of improved longevity or resolution of extra-hepatic manifestations by curing their hepatitis C.
For the sake of simplicity, combination therapies are commonly identified by their commercial trade names rather than by their specific components using the generic names. The following single or combination therapies are currently available according to their trade names and generic components (alphabetical order):
Epclusa: sofosbuvir + velpatasvir
Harvoni: sofosbuvir + ledipasvir
Viekira Pak: ombitasvir + paritaprevir + ritonavir + dasabuvir
Zepatier: elbasvir and grazoprevir
These drugs target the HCV NS3/4A protease (the “-previrs”), the NS5A nonstructural protein (the “-asvirs”) and the NS5B polymerase (the “-buvirs”). In NS5A and NS5B inhibitors seem to have fewer side effects than the protease inhibitors.
The drugs are very expensive and generally not stocked by hospital pharmacies. For this reason, patients admitted to the hospital for any reason while on therapy need to bring their medications from home (or have someone get them) to avoid missing treatment days. Optimal compliance is essential for achieving cure with these agents.
Treatment is usually 12 or 24 weeks depending on the HCV genotype, presence of cirrhosis or prior treatment failure. Sustained virological response (SVR, or cure) is defined as negative testing for HCV RNA 12 weeks or more after completing therapy.
A. Immediate management.
Since neither acute nor chronic hepatitis C present as acute liver failure, treatment and management of hepatitis C is done as an outpatient in a clinic setting.
B. Physical Examination Tips to Guide Management.
Chronic hepatitis C is generally asymptomatic. Abnormalities on physical exam will be found only in patients with cirrhosis or extrahepatic involvement.
Findings suggestive of cirrhosis include jaundice, parotid gland enlargement, gynecomastia, firm nodular liver on palpation, ascites, abdominal collaterals, pedal edema, muscle wasting, palmar erythema, asterixis.
Findings of extrahepatic involvement i.e., cryoglobulinemia include palpable purpura (usually in the lower extremities).
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
HCV infection is not managed as an inpatient (except for continuation of prior therapy), but if a new diagnosis is made on an inpatient, baseline labs can be obtained in preparation for a follow up clinic visit that include quantitative HCV RNA and HCV genotype.
Assessment for possible cirrhosis: CBC, hepatic function panel, coagulation panel (INR).
D. Long-term management.
Patients with any type of cirrhosis including HCV should undergo regular surveillance for hepatocellular carcinoma (HCC) and esophageal varices. Current guidelines specify that HCC surveillance should be done by imaging with ultrasound, or in certain circumstances dynamic contrast CT or MRI, every 6-12 months. Serum alpha-fetoprotein (AFP) is no longer recommended as part of routine HCC surveillance. The interval between upper endoscopies to identify and monitor varices is less certain, but every 2-3 years is considered adequate. When patients are hospitalized for any reason, this is sometimes a good opportunity to undertake this surveillance testing if it is overdue, especially if compliance with clinic visits and testing has been a problem.
Patients with chronic HCV should be monitored at least every 6-12 months for disease progression. Laboratory evaluation should include a hepatic function panel, CBC, and INR. Progression to cirrhosis warrants endoscopic screening for esophageal varices and imaging for hepatocellular carcinoma screening.
All patients with chronic hepatitis C should be tested for immunity to hepatitis A (anti-HAV total) and hepatitis B (anti-HBs) with administration of vaccines if needed.
Use of alcohol should be strongly discouraged as this will accelerate progression to cirrhosis.
All patients should be counselled and educated regarding the modes of disease transmission, and advised for precautions needed to prevent disease transmission to close personal contacts. Patient education materials are available at http://www.cdc.gov/hepatitis/hcv.
Consumption of raw or undercooked seafood such as oysters, shellfishes have been linked to development of life threatening vibrio vulnificus infections in patients with chronic hepatitis C. Patients with liver disease, including chronic hepatitis C, should be warned to avoid eating raw or undercooked shellfish.
In some studies, regular coffee consumption (>3 cups per day) was associated with a lower rate of disease progression, and a reduced risk of HCC development. How this finding should be incorporated into patient education is uncertain other than to provide reassurance to coffee drinkers that they are safe to continue doing so.
E. Common Pitfalls and Side-Effects of Management
With the development of DAAs that do not require use of interferon, all patients with confirmed chronic HCV and no other life-threatening comorbidities (e.g., advanced malignancy) should be referred to a liver specialist for treatment. Most patients experience little to no side effects during treatment. Those who achieve SVR have significantly decreased risk of progression to cirrhosis or worsening of liver function if already cirrhotic at the time of treatment. The risk for hepatocellular carcinoma likely also declines when HCV is cured.
No effective vaccine is available for prevention of HCV infection.
IV. Management with Co-Morbidities
HCV-HIV coinfected patients progress to cirrhosis more rapidly and have greater overall mortality. Treatment of HCV should be done in collaboration with HIV specialists. There are drug-drug interactions with the available DAAs; thus, choosing the appropriate HCV antiviral regimen will be dependent on the HIV antiretroviral medication the patient is taking. Careful review of medications is needed to identify possible drug interactions.
Post- liver transplant HCV
HCV recurs in nearly all patients who receive liver transplants who did not receive antiviral therapy prior to transplant. The risk of progression to cirrhosis in the transplanted liver is greater than a non-transplant patient. Therefore, antiviral therapy should be considered as soon as clinically feasible. Not all DAAs are available for use in post-transplant patients due to drug interactions with immunosuppression, notably calcineurin inhibitors.
All aforementioned DAAs regimens are safe to use for mild renal impairment (CrCl >30 ml/min) with no dose adjustments required.
Patient with severe renal impairment (CrCl < 30 mL/min) or end-stage renal disease (ESRD) with genotypes 1 and 4 can be treated with Zepatier with no dose adjustments needed. Those with genotypes 2, 3, 5, or 6 cannot currently be treated with the antiviral agents available.
V. Patient Safety and Quality Measures
In addition to traditional risk groups, the latest guidelines from CDC recommend one-time testing for all persons born during 1945-1965 without prior ascertainment of HCV risk. Studies have shown that point of care testing in urban hospital emergency departments can also identify a substantial number of new cases. All newly detected HCV cases should be referred to a specialist for further evaluation and consideration for antiviral treatment.
All patients with chronic hepatitis C should be tested for hepatitis A and hepatitis B and if found negative, should be vaccinated against hepatitis A and B as per the standard protocol.
All patients with chronic hepatitis C should be counselled on the risk of transmission to minimize transmission to others:
Patients should be informed about the low but present risk for transmission with sex partners.
Sharing personal items that might have blood on them, such as toothbrushes or razors, can pose a risk to others.
Cuts and sores on the skin should be covered to keep from spreading infectious blood or secretions.
Donating blood, organs, tissue, or semen can spread HCV to others.
HCV is not spread by sneezing, hugging, holding hands, coughing, sharing eating utensils or drinking glasses, or through food or water.
Patients may benefit from a joining support group.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
All patients with chronic HCV infection should be tested for antibodies to hepatitis A (anti-HAV total) and hepatitis B (anti-HBs).
All patients with chronic HCV infection who lack antibodies to hepatitis A and B should be offered vaccination against these viruses.
All patients with chronic HCV should be advised to abstain from alcohol consumption.
No recommendations can be made for the use of herbal products (insufficient evidence).
All patients with cirrhosis should be screened for HCC by abdominal ultrasound every 6-12 months.
All patients with cirrhosis should be screened for esophageal varices with upper endoscopy, and repeated every 2-3 years if negative.
VI. What's the evidence?
Panel, AIHG. “Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus.”. Hepatology. vol. 62. 2015. pp. 932-54.
MMWR 2012. vol. 61. pp. 1945-1965.
Modi, AA,, Feld, JJ,, Park, Y. “Increased caffeine consumption is associated with reduced hepatic fibrosis.”. Hepatology. vol. 51. 2010. pp. 201
Gane, EJ,, Stedman, CA,, Hyland, RH. “Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.”. N Engl J Med. vol. 368. 2013. pp. 34
Jacobson, IM,, Gordon, SC,, Kowdley, KV. “Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.”. N Engl J Med. vol. 368. 2013. pp. 1867
Scott, D., Holmberg,, M.D., M.P.H.,, Philip, R., Spradling,, M.D.,, Anne, C., Moorman,, M.P.H., and, Maxine, M., Denniston,, M.S.P.H.. “Hepatitis C in the United States.”. N Engl J Med. vol. 368. 2013. pp. 1859-1861.
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- Hepatitis C
- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has hepatitis C?
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic hepatitis C.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- Renal Insufficiency.
- V. Patient Safety and Quality Measures
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.