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Guideline: Evaluation of Abnormal Liver Chemistries | Approach to the patient with abnormal liver tests


Approach to elevated liver tests:
Elevated liver function tests (LFTs) are a very common problem in the clinical practice, since these tests are being taken routinely in the laboratory diagnostics.
Liver function tests include:
-          Enzymatic tests: aminotransferases AST (GOT) and ALT (GPT), alkaline phosphatase APH, and gamma-glutamyl transpeptidase gGT
-          Synthetic tests: Albumin and prothrombin time (Quick)
-     Bilirubin levels:  Liver’s ability to detoxify metabolites and transport organic anions into bile 
It is an important part of evaluating patients with elevated LFT, and the history must have questions about these points:
-          Complete medical history including over-the counter-medication and herbal products:
-          Alcohol consumption
-          Weight loss, fever, night sweat (B-Symptoms)
-          Another accompanying symptoms such as:
urine and stool color
jaundice and pruritis
arthralgias, myalgias, and rash
-          possible parenteral exposures including transfusions, intravenous, tattoos, and sexual activity
-          Travel history, contact to people with liver disease or with jaundice
-          Sudden pain at upper right quadrant of abdomen accompanying with jaundice and/or fever/chills suggests cholangitis or choledocholithiasis
-          Jaundice with Weight loss and palpable mass on the upper right quadrant may suggest pancreas head carcinoma
-          arthralgias and myalgias predating jaundice, for example, suggests viral or drug-related hepatitis

Clinical examination:
It is important to look for signs of chronic liver disease such as:
-          spider nevi, palmar erythema, gynecomastia, and caput-medusae
-          signs of heart insufficiency may suggest the hepatic congestion
-          the abdomen examination should test the size of the liver, its consistency, the size of the spleen, and the presence or absence of ascites, pain, and tenderness
-          the presence of jaundice and ascites suggests liver cirrhosis
-          enlarged liver with mild tenderness may be seen in viral, alcoholic hepatitis or congestion lever
-          severe tenderness with respiratory arrest on inspiration (murphy’s sign) cholecystitis or cholangitis

Laboratory tests:
In general, there are to patterns of abnormal LFTs:
1-      elevated transaminases reflecting hepatocellular injury
2-      a pattern reflecting cholestasis: elevated APH, and/or bilirubin (can be seen in both patterns)
liver function can be revealed through albumin and prothrombin time:
low albumin suggests a chronic problem
prolonged prothrombin time may be caused due to cholestasis and vitamin K malabsorption  or due to severe hepatocellular injury (in this case: no improvement on parenteral Vitamin K).

chronic (defined as six months or greater), mild elevation (defined approximately as less than five times the upper limit of normal).
The evaluation of chronic mild elevated LFTs can be achieved in a stepwise way to minimize the costs of unnecessary tests.
To identify causes; medicine, alcohol, hepatitis B or C, hemochromatosis, and NASH.
1-      Medicine:
This can be achieved through a complete history of medicine prescription one as well as over the counter or herbal products
Common causes include nonsteroidal anti-inflammatory drugs, antibiotics, statins, antiepileptic drugs, and antituberculous drugs

Features suggesting drug toxicity include lack of illness prior to ingesting the drug, clinical illness or biochemical abnormalities developing after beginning the drug, and improvement after the drug is withdrawn

2-      Alcohol:
A history of alcohol consumption with details about (amount and frequency) is important
Features suggesting BUT not specific for alcoholic liver injury includes:
-          AST/ALS ratio >2 and gGT is about tow fold elevated
-          AST NOT above 8 folds and ALS NOT above 5 folds.
3-      Hepatitis B:
History of parenteral exposures including transfusions, intravenous, tattoos, and sexual activity are important.
The laboratory which should be taken:
HBsAg (surface antigen), Anti HBs-AG (surface antibody), Anti-HBc (core antibody).
HBV-DNA and HBe-AG/Anti-HBe should be taken by chronic infection pattern
The following table shows the different result possibilities of these tests.
Inactive carrier
Chronic infection with viral replication
Chronic infection







4-      Hepatitis C:
History of parenteral exposures including transfusions, intravenous, tattoos, and sexual activity are important.
The laboratory which should be taken:
Anti-HCV and if elevated HCV-RNA-PCR

5-      Haematochromatmesis:
Iron/TICB> 45% and Ferritin > 400 ng/ml men and 300 ng/ml women è C282Y-Gyn mutation èLiver biopsy
A hepatic iron index (hepatic iron concentration in micromoles per gram dry weight divided by the patient's age) greater than 1.9 is consistent with hemochromatosis
A liver biopsy is not necessary for patients with genotypically defined hemochromatosis, normal liver biochemical tests, and serum ferritin <1000 ng/mL.

6-      Hepatic steatosis and steatohepatitis AST/ALT < 1
the differentiation between steatosis and NASH requires a liver biopsy. Nevertheless, because of the absence of effective medical therapy for NASH, we do not advocate a liver biopsy unless one of the following is present:
·         Peripheral stigmata of chronic liver disease
·         Splenomegaly
·         Cytopenia
·         Abnormal iron studies
·         Diabetes mellitus and/or significant obesity in an individual over the age of 45
Step two:
If the forementioned causes of aminotransferase elevations are excluded, the next set of tests should look for non-hepatic causes of elevated aminotransferases, which include principally muscle disorders, thyroid disease, celiac disease, and rarely adrenal insufficiency.
1-    Muscle disorders AST/ALT> 3 bis 10000/850, CK, LDH, Aldolase are elevated
2-      celiac disease: IgA transglutaminase antibodies
AST< ALT, the serum AST ranges from 29 to 80, and the serum ALT ranges from 60 to 130
3-      Adrenal insufficiency (Addison disease): Aminotransferase elevation (1.5 to 3 times the upper limit of normal
normalize within one-week following appropriate treatment
Step three:
The next set of tests is aimed at identifying less common liver conditions.
1-      Autoimmunhepatitis: young women
Serum E’phorese gGT two-fold suggestive
Liver biopsy
2-      Wilson disease: 3-80 years old:
serum ceruloplasmin level, which will be reduced by approximately 85 percent of patients.
Kayser-Fleischer rings.
24-hour urine collection for quantitative copper excretion. A value greater than 100 mcg/day is suggestive of the diagnosis.
Liver biopsy: 250 mcg/gm dry weight of liver.
3-      A1-Antitrypsin deficiency:
Alpha-1 antitrypsin in serum can be detected either by direct measurement of serum concentrations or by the absence of the alpha-1 peak on a serum protein electrophoresis
4-      Adult bile ductopenia
< 1.2 bile duct cut in cross-section per portal triad (norm 1.5-2)

Step four:
A liver biopsy

Whom to observe :
Patients in whom the ALT and AST levels are less than twofold elevated and no chronic liver, condition has been identified by the above noninvasive testing. 

Whom to biopsy:
Patients in whom the ALT and AST are persistently greater than twofold elevated. While it remains unlikely that the biopsy will provide a diagnosis or lead to changes in management, it is often reassuring to the patient and clinician to know that there is no serious disorder. 

The first step is to know which kind of bilirubin is predominant:
1-    Conjugated bilirubin: elevated in overproduction, impairment of uptake, or impaired conjugation of bilirubin.
2-    conjugated bilirubin is due to decreased excretion into the bile ductules or leakage of the pigment from hepatocytes into the serum. 

Unconjugated hyperbilirubinemia:
That can be divided into two groups:

1- Overproduction:
-          Hemolysis: characterized by low Haptoglobin, reticulocytes elevated, LDH elevated blood smear with signs of hemolysis.
Can be inherited or acquired:
·         Inherited causes of hemolysis: 
In this case is the bilirubin usually not higher than 5 mg/dl.
-          Spherocytosis
-          sickle cell disease
-          deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase
·         acquired causes of hemolysis:
-          microangiopathic hemolytic anemia (eg, hemolytic-uremic syndrome).
-          paroxysmal nocturnal hemoglobinuria
-          immune hemolysis.
-          Ineffective erythropoiesis: occurs in cobalamin, folate, and iron deficiencies.
2- Impaired hepatic uptake or conjugation:
By the absence of hemolysis.
-          Drugs: eg. rifampicin
-          Gilbert's syndrome:
a common a genetic disorder associated with unconjugated hyperbilirubinemia.
Impaired conjugation of bilirubin is due to reduced bilirubin uridine diphosphate (UDP) glucuronosyltransferase activity.
serum levels almost always less than 6 mg/dL. 
In an otherwise healthy adult with mildly elevated unconjugated hyperbilirubinemia and no evidence of hemolysis, the presumptive diagnosis of Gilbert's syndrome can be made without further testing.
-          Crigler Najjar type I: is an exceptionally rare condition found in neonates and is characterized by severe jaundice (bilirubin >20 mg/dL) and neurologic impairment due to kernicterus.
-          Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels that range from 6 to 25 mg/dL. Bilirubin UDP glucuronosyltransferase activity is typically present but greatly reduced. Bilirubin UDP glucuronosyltransferase activity can be induced by the administration of phenobarbital. 
Conjugated hyperbilirubinemia:
to be seen in two conditions:
-          Dubin-Johnson syndrome and Rotor syndrome.
-          Patients with both conditions present with asymptomatic jaundice typically in the second decade of life. The defect in Dubin-Johnson syndrome is altered hepatocyte excretion of bilirubin into the bile ducts, while Rotor syndrome appears to be due to defective hepatic reuptake of bilirubin by hepatocytes
-          Dubin-Johnson syndrome and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia in the absence of other abnormalities of standard liver biochemical tests.
Normal levels of serum alkaline phosphatase and gamma-glutamyl transpeptidase help to distinguish these conditions from biliary obstruction. Differentiating between these syndromes is possible but clinically unnecessary due to their benign nature.

Serum alkaline phosphatase is derived predominantly from the liver and bones.

Physiologically can it elevated by:
-          Pregnancy in third trimester
-          Childhood due to osteoblastic activity
-          Gradually by age from 40 to 65 especially by women
-           After fatty meals by blood types B/O
The first step to do is to determine to wither the aPH elevation is of bone or liver origin:
-          Determine gGT or 5- Nucleotidase
-          If elevated liver is most likely
-          If not, bone is most likely
The next step is to do ultrasound and ANA-Test in blood:
1-      Do Ultrasound to assess the bile duct and liver parenchyma, when these is dilated è consider obstruction and perform ERCP/MRCP
2-      AMA in blood are to be determined, when positive è consider PBC è liver biopsy to verify the diagnosis.
3-      If both AMA and ultrasound negative è liver biopsy if:
-          aPH more than 50% elevated
-          for about six months
-          otherwise: observation

DDx by elevated aPH of liver origin:
1-      Cholestatic diseases: The most common causes include:
-          partial bile duct obstruction
-          primary biliary cirrhosis (PBC)
-          primary sclerosing cholangitis
-          Adult bile ductopenia,
-          Drugs such as androgenic steroids and phenytoin.
2-      Infiltrative diseases: include:
-          Sarcoidosis,
-          Amyloidosis
-          cancer metastatic to the liver.

Gamma-glutamyl transpeptidase:

-          Gamma-glutamyl transpeptidase is found in hepatocytes and biliary epithelial cells.
-          specificity is low
-          It can be elevated in pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes mellitus, and alcoholism, medications such as phenytoin and barbiturates.
-          Its usefulness is to confirm the liver origin of an elevated alkaline phosphatase or to support a suspicion of alcohol abuse in a patient with an elevated AST and an AST:ALT ratio of greater than 2:1).
-          An elevated GGT with otherwise normal liver biochemical tests should not lead to an exhaustive work-up for liver disease.

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Written by: Ayman Zoaa
I’m a resident doctor living in Bremerhaven-Germany, my goal here is to explain medical stuff as easy and practical as possible. My second purpose is to help those who are trying to begin specializing in Germany.About my profession, I’m 30 years old, was born in Syria on 1989, I studied medicine at the University of Aleppo between 2007 and 2013, then I traveled to Germany and began my actual work before about 3 Years. I have got my medicine certificate recognized in Germany after I had made the recognition test and the medical language test.I’m specializing in internal medicine, and then I’ll proceed to gastroenterology, and hopefully endocrinology.I find writing interesting, and it also helps me to keep my information up to date, what we- medical people - need.Let us keep in touch through singing up, and through the contact-from, i will answer your Questions gladly

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