WEEK 3 SOAP NOTE

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Internal Medicine 11: 45-year-old male with abnormal liver chemistries User: Yulak Landa Email: [email protected] Date: January 09, 2021, 2020 5:22AM

Learning Objectives

The student should be able to:

Explain /understand pathophysiology of conjugated and unconjugated hyperbilirubinemia. Describe the common types of liver diseases and their risk factors (including inherited and acquired). Obtain an appropriate history to elicit risk factors for viral hepatitis. Use and be familiar with the CAGE screening tool for alcohol abuse. Identify when to order laboratory tests for evaluation of liver disease and when a liver biopsy might be indicated.

Knowledge

Historical Features to Obtain in a Patient with Abnormal Liver Enzymes

To begin the evaluation of elevated liver enzymes, a comprehensive history and physical should be done to look for signs and symptoms of liver disease. The first tests that should be ordered are additional liver function tests to confirm that the results are consistently elevated. It is important to note that the normal range for most laboratory tests is + or - 2 standard deviations. That means that 2.5% of all patients will have normal values above the upper limit of normal in the absence of disease.

Historical elements that would be pertinent in a patient with abnormal liver enzymes would be:

Jaundice and pruritus are common symptoms of cholestasis. Significant liver disease can be associated with weight loss and fever. Rectal bleeding can occur with liver disease due to portal hypertension in the hemorrhoidal veins. Dark brown urine due to urinary excretion of bilirubin Light-colored stools due to biliary obstruction Abdominal pain Diarrhea Increased abdominal girth Edema Nausea Vomiting, with or without hematemesis Altered mental status

History Indicating Increased Risk of Liver Disease

Alcohol use Regular alcohol use points towards alcoholic steatohepatitis.

Family history of liver disease

A family history of liver disease may reveal a patient at risk for Wilson disease, hemochromatosis, alpha-one antitrypsin deficiency, and Gilbert syndrome.

Blood transfusions

Blood transfusions or solid organ transplant before 1992 and clotting factor transfusions before 1987 are risk factors for hepatitis C infection, as is occupational exposure to needle sticks from HCV-positive blood.

Consumption of contaminated food

Consumption of uncooked HAV-contaminated food or water is a risk factor for acquiring hepatitis A. Common sources are fruit, shellfish, vegetables, ice and water.

Diabetes Diabetes increases the risk for non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD) of the liver.

HIV The actual risk of sexual transmission of hepatitis C is thought to be relatively low, likely much less than 1% per year among monogamous couples. Transmission of hepatitis C among males having sex with males is most likely to occur with human immunodeficiency virus (HIV) co-infection.

Injection drug use

Injection drug use is the biggest risk factor for hepatitis C transmission.

Other important history includes vaccination history, specifically for hepatitis A and B.

Bilirubin

Production & Metabolism

Around 4 mg/kg of bilirubin is produced in the human body each day. Bilirubin is created from the normal breakdown of senescent red blood cells. The bilirubin metabolites are then conjugated by the liver, allowing secretion into bile for elimination.

Measurement

Measured bilirubin is divided into direct and indirect fractions. The direct fraction provides an approximation of the conjugated bilirubin. The indirect is the difference between the total and the direct and provides an estimate of the unconjugated bilirubin.

Hyperbilirubinemia

There are essentially three mechanisms by which bilirubin is elevated:

1. increased production

Hemolysis increases the production of bilirubin and the resulting bilirubin is unconjugated. This process occurs in hemolytic anemias, hereditary spherocytosis, sickle cell disease, thalassemia, or G6PD deficiency.

2. intrahepatic causes

Intrahepatic causes of hyperbilirubinemia are divided into those with unconjugated bilirubin and those with conjugated bilirubin.

Elevation of unconjugated bilirubin is seen with Gilbert's disease, a benign hereditary decrease in the enzyme glucuronosyltransferase that leads to decreased hepatocyte uptake of heme. Bilirubin in Gilbert's disease tends to increase during stress, illness and fasting. The changes are transient and benign.

Intrahepatic causes of conjugated hyperbilirubinemia are usually due to inflammation that disrupts bilirubin transport or due to hepatocyte dysfunction. This can be acute, as in the case of toxin injury, ischemic injury, drug injury, or acute viral hepatitis. It can be chronic, as is the case in chronic viral hepatitis, alcoholic hepatitis, Wilson disease, hemochromatosis, non-alcoholic steatohepatitis, alpha-1-antitrypsin deficiency, and autoimmune hepatitis. There are two rare hereditary conditions that cause decreased excretion of bilirubin from hepatocytes: Dubin-Johnson syndrome and Rotor syndrome.

Stasis of bile within the small bile ducts (intrahepatic cholestasis) can be caused by primary biliary cirrhosis, primary sclerosing cholangitis, drugs or toxins, granulomatous diseases, sepsis, pregnancy, viral or alcoholic hepatitis, malignancy, graft vs. host disease, or liver transplant.

3. posthepatic causes

Finally, bilirubin metabolism is altered if there is obstruction of the bile drainage (extrahepatic cholestasis). This is seen in gallstones, tumors, primary sclerosing cholangitis, neoplasms, and pancreatitis.

Hyperbilirubinuria

Bile (mainly conjugated bilirubin) is converted to urobilinogen by intestinal bacteria. Most of the urobilinogen is excreted in feces or reabsorbed and transported back to the liver to be converted back into bile. The remaining urobilinogen (about 1% of total) is excreted in the urine. In patients with elevated serum bilirubin, only conjugated bilirubin will be present in urine. Hyperbilirubinuria is thus indicative of hepatobiliary disease, or rarely, inherited defects in excretion, such as Dubin-Johnson syndrome and Rotor syndrome.

Acetaminophen Toxicity

Acetaminophen toxicity is associated with acute liver hepatotoxicity with excessive ingestion, accidental or intentional. It is a dose-dependent toxin. In adults, toxicity can occur with acetaminophen doses of > 4 grams/day, although most cases occur in patients taking > 10 grams.

Medications That Commonly Cause Elevated Aminotransferases

Statins, as a class of drugs, have a reported incidence of elevated liver enzymes of 0.5% to 3%. This elevation usually occurs within the first three months of therapy and is dose-dependent. The U.S. Food and Drug Administration (FDA) no longer recommends routine monitoring of liver enzymes after starting statins, as this does not appear to be effective in detecting or preventing serious liver injury. Aminotransferase levels should be obtained before starting statin therapy and then only as clinically indicated thereafter.

Anti-epileptic medicines, including phenytoin and carbamazepine, also cause elevated liver enzymes. Other medications associated with liver injury include isoniazid, ketoconazole, and NSAIDs (though NSAID-induced hepatotoxicity is very rare).

Ask all patients about the use of herbal and over-the-counter medicines. Liver enzymes can be increased with many herbal remedies, including chaparral, ephedra, lady's mantle, senna, shark cartilage, and skullcap herb.

Liver enzymes can also be increased with the use of anabolic steroids, cocaine, PCP, and glue-sniffing. These types of uses should be asked about if no other explanation is found for elevated liver enzymes.

Genetic Liver Diseases That Cause Elevated Aminotransferases

Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease or nonalcoholic steatohepatitis resembles the inflammation of alcoholic liver disease but occurs in the absence of alcohol use.

Risk factors

Obesity, male sex, type 2 diabetes, & hyperlipidemia

Of patients with both obesity and diabetes, 100% will have mild liver inflammation, 50% will have steatohepatitis, and 19% will have cirrhosis, making these diagnoses the most common causes of cirrhosis in the United States and other industrialized nations.

Symptoms Most of the patients are asymptomatic and diagnosis is suspected from abnormal aminotransferases.

Studies The liver will show fatty infiltration on ultrasound. The diagnosis is suspected by the clinical picture and imaging.

Diagnosis Confirmation and staging is done with liver biopsy.

Management Lifestyle modifications, particularly weight loss and exercise.

Metformin and thiazolidinediones have been shown to improve aminotransferases and reduce the deposition of fat in the hepatocytes.

Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency is a cause of emphysema in the young. It is also a rare cause of elevated liver enzymes. Associated findings: It is associated with a low level of the alpha-1 antitrypsin enzyme. Diagnosis: Genetic tests confirm the condition.

Hemochromatosis

Hemochromatosis is a genetic multi-organ iron deposition disorder. It is associated with bronzing of the skin, diabetes, liver disease, heart failure, hypogonadism, and arthritis. All of these symptoms are due to an autosomal recessive genetic defect of the HFE gene. It occurs with a frequency of 5:1,000 in patients of European descent. Associated findings: Hemochromatosis is associated with an extremely elevated ferritin level (>1000 ng/mL), but ferritin is an acute-phase reactant (meaning it will increase with any acute stress on the body). Screening: The initial screen should measure transferrin saturation, calculated by dividing the serum iron by the total ironbinding capacity. A percentage greater than 45% is very suggestive. Diagnosis: The currently recommended, noninvasive way to confirm the diagnosis is with genetic testing. In the past, liver biopsy was required, but

this has been largely replaced with genetic testing.

Wilson disease

Wilson disease is a genetic disorder of biliary copper excretion leading to copper deposition in the liver and other organs. Associated findings: It usually presents in the young adult with asymptomatic elevation of liver enzymes and can progress to neuropsychiatric changes as the patient ages. Kayser-Fleischer rings are usually seen on eye examination. Screening: The initial screening test is ceruloplasmin which should be decreased. Diagnosis: The next test to evaluate would be a 24-hour urinary copper with the final confirmatory test being a liver biopsy. Too many genetic

defects make genetic testing currently not feasible.

Autoimmune Hepatitis

More common in:

females than males people with other autoimmune diseases

However, since it can have an indolent course, it should be considered in a patient with asymptomatic liver enzyme elevations.

Alcoholic Liver Disease

Alcoholic liver disease is a spectrum from fatty liver -> alcoholic hepatitis -> alcoholic cirrhosis. 15-20% of people who abuse alcohol chronically will develop hepatitis or cirrhosis or both. It usually requires six to eight drinks a day for several years to develop. Females require much less and are more susceptible. Hepatitis C dramatically increases the rate of alcohol injury to the liver.

Alcoholic hepatitis is associated with fatigue, anorexia, and weight loss. It can lead eventually to portal hypertension, GI bleeding, ascites, and hepatic encephalopathy. Cirrhosis can occur before, with, or after hepatitis.

Interviewing Patients About Alcohol Use

CAGE

It is important to get an exact amount and frequency of alcohol use. A person with more than one positive response to the CAGE questions is considered at risk for alcohol abuse or dependence:

Have you ever tried to Cut back on your drinking?

Have you every gotten Angry if someone criticized your drinking?

Do you feel Guilty about how much you drink?

Have you ever needed an Eye opener in the morning to prevent getting withdrawal or to calm your nerves?

AUDIT

The Alcohol Use Disorders Identification Test (AUDIT) is another screening test that may be used to obtain more qualitative information about a patient's alcohol consumption.

Learn more about this at AUDIT-C.

Interpreting Hepatitis Serologies

The presence of the hepatitis C antibodies confirms exposure to the virus in the past. The actual antibody titer does not tell you if the patient is chronically infected with hepatitis C; this serology stays positive even if the infection was spontaneously cleared by the body. The presence of chronic infection is confirmed with hepatitis C virus RNA titers.

Hepatitis C is an RNA virus, in contrast to hepatitis B, which is a DNA virus. Hepatitis B e-antigen is used in the evaluation of chronic hepatitis B to determine the activity of the virus.

There are situations where a negative antibody to hepatitis C virus (HCV) cannot exclude infection. These include acute HCV or HCV in immunosuppressed patients, such as patients with HIV and those on hemodialysis. HCV antibodies are present about eight weeks after infection. RNA levels become detectable one to two weeks after infection. If immunosuppression or acute infection is suspected, RNA levels should be ordered to rule out infection.

A negative HCV RNA test indicates that the infection has resolved.

Read the recommendations for testing, managing, and treating hepatitis C from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. http://www.hcvguidelines.org/. Accessed August 30, 2019.

Hepatitis Prognosis

Hepatitis C

The course of hepatitis C is variable, but approximately 80% of all people who get the virus will have chronic infection. Of the patients with chronic infection, 20% will develop cirrhosis, or scarring of the liver. Once a patient has cirrhosis, 1-4% will develop hepatocellular carcinoma, a cancer of the liver, every year.

The time for progression from acute infection to cirrhosis is approximately 20 years, but the acute infection is rarely diagnosed because it is asymptomatic. Hepatitis C is often diagnosed years after initial infection. The rate of progression is affected by certain prognostic factors.

Good prognostic signs: female sex and younger age of infection. Poor prognostic signs: male sex, later age of infection, alcohol abuse, obesity, and concomitant infection with HIV.

Hepatitis B with hepatitis C together dramatically accelerates the risk of cirrhosis.

Hepatitis B

The likelihood of acute hepatitis B to become chronic depends upon the age at which someone becomes infected. The younger a person is when infected with hepatitis B virus, the greater the chance of developing chronic hepatitis B. Approximately 90% of infected infants and 25%-50% of children infected between the ages of 1 and 5 years will develop chronic hepatitis B. The risk drops to 6%-10% when a person is infected over 5 years of age. Worldwide, most people with chronic hepatitis B were infected at birth or during early childhood.

For more information, see:

CDC. Hepatitis B FAQs for the Public. https://www.cdc.gov/hepatitis/hbv/bfaq.htm#bFAQ09. Accessed August 30, 2019.

Gathering a History of Drug Use

Clinical Skills currently?" What about asking, "You don't still use IV drugs do you?" This is a leading question and a patient who is actively using drugs is less likely to

admit to drug use if asked in this way. You should ask in an open-ended manner.

"How often are you currently using?"

It is important to learn the types of drugs, frequency, and route that the patient uses for drug administration.

"Have you ever shared needles when you injected heroin?"

It is important to educate patients who use injection drugs or are sexually active about the risks of acquiring viral hepatitis and HIV from needle sharing and unsafe sexual practices and to teach them about preventing exposure to these infections.

Even though patients may no longer be active drug users, if they have never been screened for viral hepatitis or HIV, they should be tested now, as many people can be asymptomatic for long periods of time.

Note: The USPSTF also recommends all adults aged 18 to 79 years be screened for hepatitis C.

"Have you ever been tested for hepatitis and HIV?"

Ask if the patient has been tested for infectious complications of injection drug use. Injection drug use is a significant risk factor for infectious diseases, primarily hepatitis C and HIV. Hepatitis C is present in 50-90% of all persons with a history, present or past, of injecting drugs. HIV is much less prevalent with reported rates of 2-3% of all users. Hepatitis C has a much greater infectivity per injection. Hepatitis C risk is most associated with duration of injection use and with sharing of needles. HIV risk is more closely associated with risky sexual behaviors while under the influence of drugs.

Management

Hepatitis C - Secondary Prevention

Instructions for patients with Hepatitis C

1. Abstain completely from all illicit drugs and from all alcohol. The combination of alcohol and hepatitis C dramatically speeds up cirrhosis. 2. Be aware of medicines like acetaminophen that are cleared by the liver. Only take acetaminophen sparingly. 3. Vaccination against hepatitis A and B.

99% to 100% of adults have protective levels of hepatitis A antibody five-eight years after receiving two doses of vaccine.

Chronic Hepatitis C Treatment

Genotype 1: Newer direct acting antivirals (DAA) were FDA approved in 2016, including the second generation HCV protease inhibitors elbasvir and grazoprevir. These new medications are used together and are more effective than earlier DAA medications but are very expensive.

Genotype 2 and 3: Sofosbuvir (an HCV polymerase inhibitor) along with ribavirin are the usual treatment regimen.

Guidelines from the American Association for the Study of Liver Diseases and Infectious Diseases Society. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org. Accessed August 30, 2019.

Studies

Liver Chemistries

"What drugs are you using

This is a good way to ask about current drug use, particularly in a patient who has admitted to past drug use. Patients can be very defensive about the use of illegal drugs, likely for fear of legal ramifications. It is helpful to ask for information in such a way that you assume the patient is actively using. It is easier for them to discuss type and frequency of use without being asked to admit or deny use.

A detailed history that includes prescription and over-the-counter medications, and a thorough physical examination can help us decide which liver chemistries to order. The pattern of the liver chemistry abnormalities may often identify the cause of the liver disease.

Commonly ordered liver chemistry tests include:

Bilirubin Aspartate transaminase (AST, formerly referred to as serum glutamic-oxaloacetic transaminase, SGOT) Alanine transaminase (ALT, formerly called serum glutamic-pyruvic transaminase, SGPT) Gamma-glutamyl-transpeptidase (GGTP) Alkaline phosphatase

AST and ALT are an excellent marker of hepatocellular injury. They are also found in non-hepatic sources such as skeletal and cardiac muscle. Common causes of elevated AST and ALT include non-alcoholic and alcoholic fatty liver disease, chronic hepatitis B and C, autoimmune liver disease, hemochromatosis and Wilson disease. An AST/ALT ratio greater than 2 may suggest alcoholic liver disease, especially when the GGTP is elevated. The AST, ALT, and alkaline phosphatase tests can be helpful to distinguish between hepatocellular and cholestatic disease.

The American College of Gastroenterology (ACG) has developed Clinical Guideline: Evaluation of Abnormal Liver Chemistries.

Evaluating for Autoimmune Hepatitis

Autoimmune hepatitis has a female-to-male predominance of 4:1. It is more common in patients with other autoimmune diseases (type 1 diabetes, thyroiditis, etc.). It leads initially to an indolent liver inflammation and elevated aminotransferases and can progress to fulminant liver failure. The actual level of aminotransferases is not helpful as they can start out with minor elevations and increase with time.

A screening test for autoimmune hepatitis would be elevated serum globulins, usually twice normal. Elevated globulins are sensitive but not specific, and should be followed by further testing.

There are two types of autoimmune hepatitis. Type I autoimmune hepatitis is associated with high levels of ANA and anti-smooth muscle antibody. Type II autoimmune hepatitis is a much rarer disorder and is associated with elevated levels of anti-liver kidney microsomal antibody (anti-LKM ab) and anti-liver cytosol antibody (anti LC ab). All of these autoantibodies have a low sensitivity and specificity for the disease.

The only definitive diagnostic test is liver biopsy. Diagnosis is critical because the majority of cases will respond to treatment with prednisone or azathioprine. Liver transplant is an option for patients that fail treatment.

Alcoholic Hepatitis Liver Enzyme Pattern

Alcoholic hepatitis is commonly associated with AST twice that of ALT (80% of patients). This pattern is due to low serum activity of alanine aminotransferase (ALT) because of alcohol-related decrease in pyridoxal 5-phosphate activity. It is rare to have transaminases greater than 10 times the upper limit of normal. The level of aminotransferases does not correlate with degree of hepatitis. The level of bilirubin and prothrombin time, in contrast, do correlate with degree of liver injury.

Recommended Workup of Suspected Hepatitis or Alcoholic Liver Disease

Prothrombin Time and Albumin

Prothrombin time may be prolonged and albumin may be reduced if the liver is not synthesizing proteins adequately.

HIV If there is a history of injection drug use, the patient should be tested for HIV. HIV is commonly co-transmitted with hepatitis C among injection drug users.

Iron studies To identify hemochromatosis, iron studies, consisting of serum iron, total iron binding capacity (TIBC), and ferritinshould be part of the initial evaluation of elevated aminotransferases.

Right upper quadrant ultrasound

A right upper quadrant ultrasound is often quite helpful in evaluating the presence of cirrhosis (small, nodular liver) and abnormalities of the biliary tree. If the suspicion for biliary disease is low, then other tests, such as viral serologies, would be ordered first, but ultrasound is a reasonable choice after you have confirmed that the liver chemistries are indeed abnormal.

Viral hepatitis serology

Given the history of injection drug use, it is very likely that the cause of the elevated enzymes is viral hepatitis. Approximately 3,900,000 Americans are positive for antibodies to hepatitis C and 2,700,000 Americans are chronically infected with hepatitis C. The initial evaluation for viral hepatitis should be serologic testing, which is 92-97% sensitive. Initial serology is usually done as a panel for hepatitis A, B, and C. The initial testing for hepatitis B is for the surface antigen, surface antibody, and core antibody.

A CBC should be included in the initial evaluation of abnormal aminotransferases, if it has not already been completed.

Studies not indicated at this time

Antimitochondrial antibody testing

Antimitochondrial antibody testing can be useful when evaluating for primary biliary cirrhosis, but this primarily causes elevation of bilirubin and alkaline phosphatase.

CT scan A CT scan would be more helpful for evaluating for a liver mass.

Erythrocyte sedimentation rate (ESR)

An erythrocyte sedimentation rate (ESR) is a very non-specific indicator of inflammation and would not be helpful in determining the cause of elevated transaminases.

Liver biopsy

A liver biopsy is sometimes used in the workup of liver dysfunction; however, given its invasive nature, it is usually one of the last diagnostic tests performed. Liver biopsy may be especially useful in cases where diagnosis is uncertain or in cases of suspected autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), or infiltrative diseases such as sarcoidosis or other granulomatous diseases such as tuberculosis.

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Magnetic resonance cholangiopancreatography (MRCP)

If his alkaline phosphatase and bilirubin were the predominant elevations, then evaluation of the biliary tree would be appropriate. Ultrasound should be the first imaging test in that setting. If unrevealing, a magnetic resonance cholangiopancreatography (MRCP) can provide additional imaging non-invasively. However, an MRCP is more expensive than an ultrasound.

The Role of Liver Biopsy in Hepatitis C

The role of liver biopsy in hepatitis C is changing. In all the initial studies for hepatitis C, biopsy was routinely performed. It is clear that liver biopsy gives very useful information about the stage of fibrosis and the grade of inflammation. Both of these values are predictors of prognosis.

Indications

Many experts feel that if the need for treatment is clear, e.g. there are elevated aminotransferases in a patient with genotype 2 or 3 (associated with good response to treatment), liver biopsy is not necessary. The thought is that the liver biopsy is associated with risks and sampling error may underestimate the degree of fibrosis. The result of the biopsy may not change the decision to treat the patient.

On the other hand, if a patient has normal aminotransferases but suspicion is high for fibrosis, then the result of the biopsy may change the decision to treat the patient.

Other indications for liver biopsy would be:

staging and grading of all forms of hepatitis diagnosis of Wilson disease hemochromatosis diagnosis of liver masses evaluation of abnormal aminotransferases in patients with inconclusive workup evaluation of the liver after transplantation

Risks

The most severe risk of liver biopsy is intraperitoneal bleeding and large liver hematomas. Mortality from the biopsy is 1 out of every 10,000-12,000 patients. Other complications would include pain, hypotension, pneumothorax, hemothorax, and hemobilia.

Clinical Reasoning

Differential of Abnormal Liver Chemistries in a Patient with Injection Drug and Alcohol Use

More Likely Diagnoses

Hepatitis C & B

A history of injection drug use increases the risk of viral hepatitis including hepatitis C and B. Hepatitis B and C can be transmitted through reused tattoo needles. Many liver diseases would have a normal physical examination early in the course of the disease. For this reason, viral hepatitis is often not identified for years after its acquisition. Vaccination for hepatitis B is decreasing the rates of this infection. There is no vaccination available for hepatitis C and the majority of new cases are in injection drug users.

Alcoholic liver disease

Alcoholic liver disease is fairly common and should be considered given a history of alcohol and substance use. Note, alcoholic liver disease is usually AST>ALT.

Less Likely Diagnoses

Acetaminophen (Tylenol) toxicity is a consideration, though this is usually associated with extremely elevated aminotransferases (in thousands). It can also cause a rapidly fulminant hepatitis with jaundice and loss of synthetic function. It is usually much more symptomatic. Autoimmune hepatitis is more common in females and is often associated with a family history of liver disease. Hemochromatosis is a genetic disorder causing abnormal iron deposition and can cause mild elevation in transaminases as seen here but is quite rare, occurring in approximately 0.5% in people of European ancestry and less frequently in other ethnic groups in the US. If more common diagnoses are ruled out it could be considered. Non-alcoholic steatohepatitis (NASH) more commonly occurs in patients with obesity and/or diabetes mellitus. Metastatic liver cancer is unlikely with no evidence for another primary cancer. Hepatitis A would not cause chronic viral hepatitis.

References

Centers for Disease Control and Prevention (CDC). Integrated prevention services for HIV infection, viral hepatitis, sexually transmitted diseases, and tuberculosis for persons who use drugs illicitly: summary guidance from CDC and the U.S. Department of Health and Human Services. MMWR Recomm Rep. 2012;61(RR-5):1-40.

U.S. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin

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drugs. Accessed August 30, 2019.

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