Severity Grading In Drug Induced Liver Injury – LiverTox

Last Update: May 4, 2019.

The severity of cases of drug induced liver injury can vary greatly, from mild, transient and asymptomatic elevations in serum enzyme levels to acute liver failure leading rapidly to death or need for liver transplantation. In assessing drug induced liver injury, it is important to categorize severity in an objective manner. However, the variability in manifestations of drug induced liver disease makes it difficult to use a single symptom, laboratory abnormality or outcome to grade severity of injury. As a part of ongoing studies of drug induced liver injury, the Drug-Induced Liver Injury Network (DILIN) developed a 5 point scale for grading the severity of liver injury based upon the presence of jaundice, hospitalization, signs of hepatic or other organ failure, and ultimate outcome.

• 1+, Mild: Raised serum aminotransferase or alkaline phosphatase levels or both, but total serum bilirubin <2. 5 mg/dL and no coagulopathy (INR <1.5)

• 2+, Moderate: Raised serum aminotransferase or alkaline phosphatase levels or both and total serum bilirubin level ≥2.5 mg/dL or coagulopathy (INR ≥1.5) without hyperbilirubinemia

• 3+, Moderate to Severe: Raised serum aminotransferase or alkaline phosphatase levels and total serum bilirubin level ≥2.5 mg/dL and hospitalization (or preexisting hospitalization is prolonged) because of the drug induced liver injury

• 4+, Severe: Raised serum aminotransferase or alkaline phosphatase levels and serum bilirubin ≥2.5 mg/dL and at least one of the following:

  • Prolonged jaundice and symptoms beyond 3 months, or

  • Signs of hepatic decompensation (INR ≥1.5, ascites, encephalopathy), or

  • Other organ failure believed to be related to drug induced liver injury

• 5+, Fatal: Death or liver transplantation for drug induced liver injury

Severity is also graded on the basis of symptoms, with “S” indicating symptoms believed to be caused by the liver injury and “A” absence of symptoms. Symptoms that qualify as possibly due to liver injury include fatigue, weakness, nausea, right upper quadrant pain, itching, skin rash, jaundice, anorexia or weight loss. In all situations, the symptoms should be judged as being due to the drug induced liver injury. This grading applies mostly to patients with enzyme elevations without jaundice, as it is rare for a patient with jaundice not to have symptoms.

In prospective clinical trials of medications, standard criteria are used to assess the severity of adverse events including symptoms and laboratory test abnormalities. Adverse events are typically graded on a scale of 0 to 4. Grades for severity of liver test abnormalities and symptoms of liver injury have been developed and standardized and are used in many publications of clinical trials and studies of new medications. A commonly used grading system is that developed by the Acquired Immune Deficiency Syndrome (AIDS) Clinical Trials Group (CTG). In this system, the following levels are used to assess severity, with the values expressed as multiples of the upper limit of the normal range (ULN).

FEATURE	Grade 0	Grade 1	Grade 2	Grade 3	Grade 4
ALT	<1.25	1.25-2.5	>2.5-5.0	>5.0-10	>10
AST	<1. 25	1.25-2.5	>2.5-5.0	>5.0-10	>10
Alkaline Phosphatase	<1.25	1.25-2.5	>2.5-5.0	>5.0-10	>10
GGT	<1.25	Tc_1_1_1_3″ rowspan=”1″ colspan=”1″>1.25-2.5	>2.5-5.0	>5.0-10	>10
Bilirubin	Normal	>1.0-1.5	>1.5-2.5	>2.5-5	>5

Descriptive terms are also applied to these grades, with Grade 1 indicating mild, Grade 2 moderate, and Grade 3 severe and Grade 4 life-threatening values. However, it should be stressed that these terms usually overestimate the severity of drug induced liver injury, as ALT levels of 5 to 10 times the upper limit of normal (~200 to 400 U/L) without symptoms or jaundice cannot be considered severe hepatotoxicity, and should instead be referred to as “Grade 3 ALT elevations”. The grading of liver test elevations is sometimes adjusted to baseline values, particularly in patients with underlying liver disease, such as hepatitis B or C. In these situations, Grade 0 represents values <1.25, Grade 1, 1.25-2.5, Grade 2, 2.6-3.5, Grade 3, 3.6-5, and Grade 4, >5 times baseline. This convention, however, is not always used.

A similar grading system has been developed by the Cancer Therapy Evalutation Program of the National Cancer Institute (NCI) of the National Institutes of Health, which is referred to as the Common Toxicity Criteria for Adverse Events, version 4.0: CTCAEv4.03. In this system, the following levels are used to assess severity, with the values expressed as multiples of the upper limit of the normal range (ULN).

Descriptive terms are also applied to these grades, with Grade 1 indicating mild, Grade 2 moderate, and Grade 3 severe and Grade 4 life-threatening values. However, it should be stressed that these terms usually overestimate the severity of drug induced liver injury, as ALT levels of 5 to 20 times the upper limit of normal (~400 to 800 U/L) without symptoms or jaundice cannot be considered severe hepatotoxicity, and should instead be referred to as “Grade 3 ALT elevations”. The grading of liver test elevations is sometimes adjusted to baseline values, particularly in patients with underlying liver disease, such as hepatitis B or C. In these situations, Grade 0 represents values <1. 00, Grade 1, 1.00-2.5, Grade 2, 2.6-5.0, Grade 3, 5.0-20, and Grade 4, >20 times baseline. This convention, however, is not always used.

Thus, the two grading systems have slightly different “cutpoints” to separate the different grades of injury. The AIDS Clinical Trials Group requires an enzyme elevation of at least 1.25 times the ULN to warrant the designation of Grade 1 abnormalities, whereas the NCI system uses any elevation above the ULN as Grade 1 enzyme abnormalities. Similarly, Grade 4 abnormalities in the AIDS CTG system are based on enzyme values above 10 times the ULN, whereas the NCI system uses 20 times ULN.

A problem with all grading systems using the upper limit of normal as an index is that there is little consensus on what the ULN should be or how it should be calculated. Thus, the upper limit of normal of ALT in different testing laboratories can range from 19 to 77 U/L, and some laboratories use a different reference range for women than men. Actually, current automated systems for measuring ALT values yield very similar results and use of common reference limits is reasonable, particularly in multicenter trials. In the LiverTox website, the default ULN for ALT is 40 U/L, alkaline phosphatase 115 U/L and bilirubin 1.2 mg/dL. Serum bilirubin values are particularly confusing when using multiples of the upper limit of normal, as the ULN in different laboratories may be 1.0, 1.2, or 1.5 mg/dL and a Grade 4 elevation may therefore be 10 mg/dL, 12 mg/dL or 15 mg/dL.

Normal Enzyme Levels May Hide Advanced Liver Fibrosis

by
Judith Groch,

Contributing Writer, MedPage Today

September 9, 2008

MILAN, Italy, Sept. 9 — Patients with nonalcoholic fatty liver disease but normal alanine aminotransferase (ALT) levels are still at risk of severe hepatic disease, researchers found.

More than half of such patients had advanced fibrosis, as well as altered glucose metabolism and insulin resistance, Silvia Fargion, M.D., of the University of Milan, and colleagues reported in the September issue of Hepatology.

Nonalcoholic fatty liver disease is now considered the hepatic expression of metabolic syndrome — obesity, type 2 diabetes, and dyslipidemia account for the risk of advanced liver disease, in addition to the well-established cardiovascular risk, the researchers wrote.

• Explain to interested patients that among patients with nonalcoholic fatty liver disease, the risk of developing severe disease persists despite normal liver enzyme levels.
• Explain that in the absence of a biopsy or a simple test to identify those at risk, patients require careful follow-up and lifestyle changes to reduce metabolic syndrome risks.

However, the most common criterion for referral to a liver unit is the presence of elevated liver enzymes, and only individuals with increased ALT levels have been enrolled in most nonalcoholic fatty liver disease studies.

So, the researchers said, it is uncertain whether patients with normal ALT have a milder disease and whether they should undergo liver biopsy.

To shed some light on the subject, the researchers reviewed the histological data of 458 patients with nonalcoholic fatty liver disease who underwent liver biopsy from January 2003 through June 2006.

Of these, 395 (86%) had altered liver enzymes; 63 with persistently elevated ferritin or long-lasting severe steatosis had normal ALT levels.

Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis( ≥2) were identified by multivariate analysis. Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance, ALT, and gamma-glutamyltransferase, but a higher prevalence of hypertension.

Nonalcoholic steatohepatitis was diagnosed in 59% of patients with normal ALT and in 74% of those with increased ALT (P=0.01).

In the overall series of patients, nonalcoholic fatty liver was independently predicted by ALT (odds 1. 11, 95% confidence interval 1.04 to 1.19 per 10-IU/mL increase) and diabetes (OR 1.5, 95% CI 1.1 to 2.0).

The same variables were selected in patients with increased ALT, whereas in those with normal ALT, homeostasis model assessment (HOMA-IR), and ALT were independent predictors.

Severe fibrosis was independently predicted by serum ferritin (OR 1.04, 95% CI 1.001 to 1.08 per 50-ng/mL increase), ALT (OR 1.07, 95% CI 1.02 to 1.14), and diabetes (OR 1.8, 95% CI 1.4 to 2.3) in the overall series; serum ferritin and diabetes in those with increased ALT.

However, only homeostasis model assessment (HOMA-IR) predicted more severe fibrosis in patients with normal ALT (OR 1.97, 95% CI 1.2 to 3.7).

The evidence suggests that liver biopsy might be mandatory in most cases unless sensitive and specific noninvasive tests currently unavailable prove their efficacy. However, the investigators said, this raises the question of the feasibility and cost-effectiveness of liver biopsy in an extremely large at-risk population.

At present, biopsy is rarely indicated for patients with normal ALT. For this reason there were only 63 cases with normal ALT for this study, a definite limitation, the researchers noted.

A recently proposed scoring system (NASH score) to identify patients with advanced fibrosis potentially rendering liver biopsy unnecessary in 75% of cases, found a positive predictive value of 100% and a negative predictive value of 89.6% for identifying patients with and without advanced fibrosis, respectively.

The findings from the present study suggest that the score could also be used in the general population, including in persons with normal ALT.

Diabetes and insulin resistance were factors most closely associated with severe liver disease in that population.

In addition, hypertension, a key feature of the metabolic syndrome, was surprisingly more prevalent in patients with normal ALT.

This underlines the fact that the metabolic alterations related to steatosis and to adipose tissue-related endocrine dysfunction occur independently of overt liver damage.

Study limitations included the small number of patients with a normal ALT, and the variability of liver biopsy in the sample. The large number of patients referred to the liver units for hyperferritinemia means that this patient population was not truly representative, the researchers said.

These data indicate that more than half of nonalcoholic liver disease patients with normal ALT levels have a potentially progressive liver disease, they said.

In the absence of biopsy or of an adequate score to identify those at risk, these patients could miss careful follow-up and might not be motivated to adopt lifestyle changes that might cure their liver disease and the extrahepatic manifestations of the metabolic syndrome.

Clinicians should be aware of the importance of a complete clinical evaluation for early diagnosis and treatment of liver disease, as well as the different manifestations of the metabolic syndrome, they concluded.

Secondary Source

Hepatology

Source Reference: Fracanzani AL, et al “Risk of Severe Liver Disease in Nonalcoholic Fatty Liver Disease with Normal Aminotransferase levels: A Role for Insulin Resistance and Diabetes” Hepatology 2008; 48: 792-798.

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Diagnosis of pancreatitis – blood test for lipase and amylase

Amylase and lipase are digestive enzymes. Their amount in the bloodstream is used to diagnose the condition of the pancreas in case of suspected pancreatitis. Analyzes can be carried out at the direction of a doctor or at the request of the patient, but only a specialist can interpret the results and, if necessary, prescribe treatment. To obtain the most accurate results, special preparation is required before donating blood. Within 10 hours before the tests, it is necessary to refuse to eat food, avoid significant physical exertion, stress.

Lipase test

Lipase is an enzyme that is necessary for the breakdown of fats. The results of a blood test for lipase play an important role in the diagnosis of diseases such as obstruction of the pancreatic duct and pancreatitis in acute or chronic form. Reference values ​​for this enzyme are 13-60 IU/L. If the test results are within these values, this indicates that at the moment the pathological process does not affect the pancreas.

Elevated levels of may indicate acute or chronic inflammation, neoplastic changes, traumatic damage to the pancreas, blockage of its ducts. Based on the results of one test, it is impossible to make an accurate diagnosis and choose an effective treatment method. For this, an examination is prescribed, which may include both laboratory tests and instrumental studies.

Concentration too low enzyme in the blood may indicate a decrease in the functional activity of the pancreas or cystic fibrosis.
Determining the level of lipase has a high diagnostic value in identifying various pathologies of the pancreas. The enzyme is produced only by the cells of this organ, so it can be used as a marker of its condition.

When interpreting the results, the patient’s age, clinical picture, results of other studies and other factors are taken into account.

Amylase test

Amylase is an enzyme responsible for the breakdown of carbohydrates. It, unlike lipase, is produced not only by the pancreas, but also by the salivary glands. In addition, a certain amount of the enzyme is formed in the skeletal muscles, intestines and ovaries. A blood test for amylase is prescribed for patients with acute or chronic pancreatitis, with suspicion of pathology of the ovaries or salivary glands.

In patients over 18 years of age, the enzyme level should not exceed 53 U / l. The norm for children varies depending on their age. The level of pancreatic amylase is analyzed by the doctor, taking into account the total amount of the enzyme. In acute pancreatitis, in most cases there is a significant increase in the amount of pancreatic enzyme. Sometimes the increase in indicators is insignificant or they remain within the normal range. The test results do not reflect the degree of damage to the pancreas, so a comprehensive examination is carried out to confirm the diagnosis and develop a treatment regimen. An increase in performance can be caused not only by pancreatitis, but also by traumatic damage to the pancreas, its oncology, blockage of the pancreatic duct, rupture of an aortic aneurysm, perforated ulcer, peritonitis, intestinal obstruction and other pathologies.

In acute pancreatitis amylase levels usually rise earlier than lipase levels . The lipase concentration remains high longer. To get a complete picture, a study to determine the amount of these two enzymes is carried out simultaneously.

Total serum protein, determination

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• Total protein in whey

Analysis of the content of total protein in the blood serum allows you to assess the state of protein metabolism in the human body and identify deviations from the norm. Proteins are the key building material of which organs and tissues are composed, in addition, they are an important component of hormones, enzymes, and are involved in the transport of substances between organs and tissues. Deviation from the norm of total serum protein in some cases indicates various diseases.

What is meant by total protein?

The total protein in the blood serum is the concentration of albumins and globulins, it determines the state of metabolism. Albumins are synthesized in the liver from food. Their amount in plasma affects the level of osmotic pressure, which keeps fluid inside the blood vessels. Globulins perform an immune function (antibodies), ensure normal blood clotting (fibrinogen). Proteins are also responsible for ensuring the correct acid-base balance (pH). Disturbances can occur in some physiological conditions, but in some cases they are symptoms of diseases. Absolute hypoproteinemia is a decrease in the level of protein associated with insufficient intake or an increase in demand. Usually it occurs due to a lack of albumin and indicates exhaustion, malnutrition, chronic intoxication.

Determination of total protein in blood serum gives the following results:

• Normal level. For adults over 18 years of age, it is 64-83 g / l.

• The total protein in serum is lowered. This may indicate malnutrition, impaired synthesis, increased protein breakdown, as well as kidney disease and other pathologies.

• Total serum protein is elevated. This condition occurs during infectious processes in acute and chronic forms, autoimmune diseases, malfunctions of the adrenal glands, and some liver diseases.

How to prepare for the examination?

Serum total protein analysis requires the following preparation rules:

• Stop smoking for at least 30 minutes before blood sampling.

• Refusal to eat for 12 hours before the study.

• Limit physical and emotional stress for at least 30 minutes before the examination.

Who is the test assigned to?

The study can be prescribed if there is a suspicion of protein metabolism disorders – they occur with various pathologies of the internal organs.