Summary
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No increase in liver enzymes is trivial
Increases in liver enzymes (transaminases and alkaline phosphatase) and bilirubin in the absence of symptoms are common. No increase in these substances is trivial.
All persistent elevations in liver enzymes require methodical evaluation and an appropriate diagnostic hypothesis.
| Characteristics of increase: cholestatic or hepatocellular |
According to their characteristics, the causes of increased liver enzymes can be classified into cholestasis problems and hepatocellular injury problems.
TABLE 1
Liver disease and associated increases in liver enzymes > Hepatocellular disease (increases in transaminases predominate) Common Less common > Cholestatic diseases (increases in alkaline phosphatase, bilirubin, gammaglutamyl transferase predominate) Common Less common Cholestatic problems tend to cause increases in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT). Hepatocellular injury increases GPT (glutamate-pyruvate transaminase) and GOT (glutamic oxalacetic transaminase) |
| How should pathological results be evaluated? |
When addressing elevations in liver enzymes, the physician should make a differential diagnosis based on the medical and social history and physical examination.
> Think about alcohol, medications and fats
The most common causes of elevated liver enzymes are the toxic effects of alcohol, medication overdose, and fatty liver.
Alcohol consumption must be verified . “Significant” drinking is defined as more than 21 glasses per week for men or more than 14 glasses per week for women over a period of at least 2 years.
The exact pathogenesis of alcoholic hepatitis is not fully understood, but alcohol is primarily metabolized in the liver and damage is likely to occur during the metabolism of consumed alcohol.
Alcoholic liver disease can be difficult to diagnose, as many people are reluctant to reveal how much they drink, but it should be suspected when the GOT:GPT ratio is 2 or greater.
In a classic study, an index greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, in 26% of patients with post-necrotic cirrhosis, in 8% of those with chronic hepatitis, 4% of those who suffered from viral hepatitis and in none of those who had obstructive jaundice. The disease can often be corrected if the patient manages to remain abstinent from alcohol over time.
A detailed medication history is important and should focus particularly on recently added medications, dosage changes, medication overuse, and use of over-the-counter drugs and herbal medicines.
Among the medications that affect liver enzymes are statins, which cause liver dysfunction especially during the first three months of treatment, nonsteroidal anti-inflammatory drugs (NSAIDs), antiepileptics, antibiotics, anabolic steroids and paracetamol. Illegal drugs and herbal medicines can cause toxic hepatitis.
Although in these cases the inflammation resolves if the causative agent is discontinued, full recovery can take weeks to months.
Relevant social history includes exposure to environmental hepatotoxins such as amatoxin (present in some fungi) and occupational hazards (eg, vinyl chloride).
Risk factors for viral hepatitis should be evaluated, including the use of intravenous drugs, blood transfusions, unprotected sexual contact, organ transplantation, perinatal transmission, and history of working in health services or traveling to areas where hepatitis A or E is endemic.
The medical and family history should include details of associated illnesses, such as:
• Right heart failure (cause of congestive liver disease)
• Metabolic syndrome (associated with fatty liver)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency
The physical examination should be exhaustive, with emphasis on the abdomen and search for signs of advanced liver disease, such as hepatomegaly, splenomegaly, ascites, edema, spider hemangiomas, jaundice, and asterixis.
Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.
> Other diagnostic studies
Given the increase in liver enzymes or the pathological physical examination, new studies should be ordered.
For cholestasis. It should be characterized as extrahepatic or intrahepatic .
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In the event of pathological results on ultrasound , other imaging studies should be ordered, for example computed tomography cholangiopancreatography or magnetic resonance imaging.
Upon confirmation of a lesion, endoscopic retrograde cholangiopancreatography is frequently ordered to obtain biopsy samples, remove obstructions, and place therapeutic stents. When endoscopic attempts fail to relieve obstruction, surgical bypass may be appropriate.
For non-hepatobiliary problems. Depending on clinical manifestations, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.
Alkaline phosphatase is found in many other types of tissues, including bone, kidney and placental tissue, and can be increased during pregnancy, adolescence and even after fatty meals. After investigating these causes, the isolated increase in alkaline phosphatase should be evaluated by GGT or 5-nucleotidase values, which are more specifically of hepatic origin.
If these are within normal limits, one should be evaluated for disorders of bone growth and cell turnover such as Paget’s disease, hyperparathyroidism, and malignancies. Stauffer syndrome should be considered in the setting of paraneoplastic elevation of alkaline phosphatase in the setting of renal carcinoma without liver metastases.
GOT and GPT values may also be increased in clinical situations and syndromes not related to liver disease.
Rhabdomyolysis , for example, can be associated with increases in GOT in more than 90% of cases and GPT in more than 75%. Markers of muscle injury, including blood creatine kinase, should be obtained when the patient suffers from heat stroke, muscle weakness, strenuous activity, or seizures, since increased GOT and GPT do not always indicate liver injury.
Given the numerous disorders that can increase liver enzymes, evaluation and treatment should focus on identifying and eliminating the causative agents and treating the process with appropriate medical therapy.
| Fatty liver |
Up to one-third of the US population (100 million people) may suffer from NAFLD
With rates of obesity and type 2 diabetes on the rise in the general population, identifying nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) requires consideration of these pathologies, as well as close coordination between primary care professionals. and subspecialists.
According to current estimates, up to one-third of the US population (100 million people) may suffer from NAFLD, and 1% to 3% of the population (4–6 million) likely suffer from NASH, which is defined as steatosis with inflammation. Patients with NASH are at risk of fibrosis, hepatocellular injury, and cancer.
NAFLD is more common among men. It is present in about 80%-90% of obese adults, in two-thirds of adults with type 2 diabetes, and in many people with hyperlipidemia. It is also becoming more common among obese children.
> Diagnosis of fatty liver
Although liver enzymes are more likely to be elevated in people with NAFLD, many of these patients may have normal enzyme values. GPT may be increased in only up to 20% of cases and is not related to the degree of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time. In contrast to alcoholic injury, the GOT-GPT index is usually <1.0.
Non-invasive methods to diagnose NAFLD are the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, GOT-GPT index. This and other algorithms may be useful in differentiating between patients with minimal fibrosis and those with advanced fibrosis.
Ultrasound is a first-line diagnostic test for fatty liver, although it can demonstrate fatty infiltration only in about 60% of cases.
CT and MRI are more sensitive, but more expensive. Transient elastography is now more popular and is associated with liver biopsy results to diagnose or rule out advanced liver fibrosis.
The gold standard for diagnosing NAFLD and NASH is to identify fat-laden hepatocytes or portal inflammation on biopsy ; although biopsy is generally reserved for cases in which the diagnosis is in doubt.
> Behavioral treatment
The main treatment for NAFLD is behavior modification including weight loss, exercise and compliance with a low-fat diet, in addition to strict control of blood glucose and treatment of any underlying lipid disorders. Studies showed that a 7% to 10% weight loss is associated with a decrease in NAFLD inflammation.
Due to the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians are of significant importance for the long-term management and treatment of patients with NAFLD.
| Other liver function disorders |
> Hereditary hemochromatosis
Hereditary hemochromatosis is the most common inherited liver disorder in adults of European ancestry and can be treated effectively if discovered early.
Its clinical diagnosis can be difficult, since many patients do not have symptoms at the beginning despite having increased liver enzymes. Initial symptoms may be severe fatigue, arthralgia and, in men, impotence, before the onset of the classic triad of “tan diabetes” with cirrhosis, diabetes and darkening of the skin.
If hemochromatosis is suspected, complementary studies should include calculation of the percentage of transferrin saturation. Saturation greater than 45% justifies measurement of plasma transferrin to evaluate iron overload (ferritin > 200–300 ng/ml in men, > 150–200 ng/ml in women). If iron overload is confirmed, referral to a gastroenterologist is recommended.
Therapeutic phlebotomy is the treatment of choice and is well tolerated by most patients.
> Chronic hepatitis due to virus B and virus C
These infections are common:
* Chronic hepatitis C virus infection. Direct-acting antiviral drugs revolutionized the treatment of hepatitis C virus (HVC) and produced a sustained viral response and presumed cure at 12 weeks in more than 95% of cases . Given new treatments that are effective and well tolerated, primary care physicians have a fundamental role in screening for CVH.
The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend screening for CVH in people with risk factors, such as:
• Exposure to HVC
• HIV infection
• Behavioral or environmental risks for contracting the virus, such as use of intravenous drugs. If the HCV antibody screen is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and procedures should be performed. Testing for genotype to guide treatment.
Although recommendations and treatments are constantly evolving, the choice and duration of treatment is determined by the viral genotype,
previous treatment history, stage of liver fibrosis and possible drug interactions.
* Hepatitis B virus (HBV) infection. Treatment for acute HBV infection is generally supportive, although viral suppression with tenofovir or entecavir may be necessary for patients with coagulopathy, hyperbilirubinemia, or hepatic failure. Treatment of chronic HBV infection may not be necessary and is generally considered for those with increased GPT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.
* Autoimmune hepatitis
Autoimmune causes of elevated liver enzymes should also be considered during the initial screening. Positive tests for antinuclear antibodies and antismooth muscle antibodies are common in cases of autoimmune hepatitis.
Autoimmune hepatitis affects women more than men, in a ratio of 4:1. The highest incidence is in adolescence and between 30 and 45 years of age.
* Primary biliary cholangitis
Elevated alkaline phosphatase should also raise suspicion of primary biliary cholangitis, an autoimmune disorder that affects the small and medium-sized intrahepatic bile ducts. The diagnosis of primary biliary cholangitis can be made with a positive test for antimitochondrial antibodies, present in almost 90% of patients.
* Primary sclerosing cholangitis
Elevated alkaline phosphatase is also pathognomonic of primary sclerosing cholangitis, which is associated with inflammatory bowel disease. Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on magnetic resonance cholangiopancreatography and confirmed by biopsy if necessary.
| Derivation |
Referral to a subspecialist should be considered if the cause remains ambiguous or unknown, if there is concern about possible rare liver disease, such as an autoimmune disorder, Wilson’s disease, or alpha-1 antitrypsin deficiency, or if evidence of liver disease is found. advanced or chronic.
Primary care physicians are at the forefront of detecting and diagnosing liver disease and close coordination with subspecialists is essential for patient care.
