Friday, February 02, 2001



Friday, February 02, 2001 Scribe: Melissa

Pathology Proof: Anita

Dr. Oliver

Liver Function Test (LFT)

The Case:

A 26 years old female presents with fever, chills, sore throat, nausea, and vomiting. She was diagnosed with strep throat and given penicillin, zantac, phenergen and sent home. Three days later, she returned with her throat feeling better, but still have nausea and vomiting (n&v). She admitted to drinking a couple of 6-packs a day (that’s what she admitted to. Who knows how much she really drinks. This is something we will find out about relatively quickly: they always underestimate how much they really drink).

← Physical exam (the second time the physician saw her).

□ Jaundice

□ Vital signs – BP 124/50 (diastolic is a little low), pulse 112, temperature 100.1, tachycardic, fever, RUQ tenderness, enlarged liver (so he ordered the lab tests)

← Liver Function Tests

□ 1) AST & ALT (aspartate amino transferase, alanine amino transferase)

▪ These are enzymes made by the hepatocytes for amino acid synthesis pathway.

▪ Indicate liver parenchymal injury when elevated.

▪ Causes: Viral hepatitis, drugs, toxins, other infections

▪ Non-specific – these values rise in virtually all liver-related phenomenon

▪ Quite sensitive – does not take much injury at all to see mild elevation in the enzymes. Also there is a good correlation between the severity of injury and the level of elevation.

□ 2) AST/ALT= Deritis ratio

▪ Usually is decreased with injury, since ALT rises more than AST.

← Injury include: viral hepatitis, toxic hepatic injury

▪ Exception: in alcoholic liver disease, the AST is > ALT so the Deritis ratio is increased.

□ 3) LDH (lactase dehydrogenase)

▪ Least specific therefore not good for differentiation of diseases. Why? a) Virtually any liver disease can cause an increase in LDH. b) Also, LDH is made in several organs. There are 5 LDH isoenzymes. (Dr. Oliver didn’t name them, but from Dr. Dunn’s lecture yesterday: liver, bone, jejunum, placenta, Regan).

▪ Hence, increased LDH level does not necessarily indicate liver disease (MI can do it; hemolysis also can do it)

▪ Degree of elevation matters most: toxic liver injury caused the greatest amount of LDH increase.

← Toxic liver injury> space-occupying lesions (tumor) > viral hepatitis> biliary obstruction congestion and even passive liver congestion

← Tests for cholestasis

□ 1) Alkaline Phosphatase (AP)

▪ AP is very sensitive, but not specific (just like LDH) because other tissues make AP (bone and others).

▪ Probably the most sensitve test for cholestasis meaning this would be the first enzyme to be abnormally increased

□ 2) gamma glutamyl transferase (GGT)

▪ We used to measure this all of the time because it is very good. No longer done thanks to revision of Medicare list of testing panels.

▪ Very sensitive and very specific for the liver. If elevated, this is diagnostic of cholestasis

□ 3) 5’ nucleotidase

▪ Similar to GGT clinically and functionally, but not used much anymore

□ 4) Bilirubin

▪ Breakdown product of heme and excreted in bile after glucuronide conjugation in the hepatocytes.

▪ Increased with hepatocellular injury, hemolysis, any biliary obstruction, congenital hyperbilirubinemias (see 2 bullets down).

▪ Indirect bilirubin = unconjugated; Direct bilirubin = conjugated (water-soluble) – the lab only reports as indirect or direct bilirubin; not conjugated or unconjugated. “NEED TO KNOW”

▪ Also NEED TO KNOW what diseases cause each: see last page.

← Unconjugated: hemolysis, Gilbert syndrome, Crigler-Najjar syndrome

← Conjugated: Biliary obstruction, Dubin-Johnson syndrome, Rotor’s syndrome (The basic difference between these two diseases is that Dubin-Johnson gives you a black liver and Rotor’s doesn’t)

← Tests of Liver Synthetic Function

□ Albumin – a measure of hepatic failure!!

▪ Made by the liver

▪ Decreases with hepatocyte loss (get decreased oncotic pressure leading to ascites)

▪ Will also be accompanied by a decrease in protein

□ PT & aPTT

▪ Prolonged due to loss of coagulation factors synthesis (which are made in the liver).

▪ PT is the more sensitive indicator of hepatic failure. (emphasized).

← Lab Data (back to the patient who will end up with fulminant hepatic failure) – Dr. Oliver spent some time reading from this and pointing out the values. I suggest looking over this table and making sure that these abnormal lab values make sense to you.

| |Day 1 | |Day 2 |Day 3 |Day 5 |Normal values |

|Alb |3 |2.5 |2.3 |2.1 |2.5 |3.9 - 5.0 |

|ALT |- |9388 |3734 |2686 |1580 |9 – 52 |

|AST |15,000 |5167 |2859 |526 |205 |14 – 36 |

|TBil |2.6 |2.5 |2.8 |2.7 |2 |0.2 – 1.3 |

|DBil |- |1.7 |1.9 |1.4 |0.4 |0.0 – 0.3 |

|AlkPhos |175 |163 |191 |167 |181 |38 – 126 |

|LDH |75590 |- |- |- |- |313 – 618 |

|PT |24.3 |- |17.4 |14.3 |- |10.4 – 13.8 |

|aPPT |34.8 |- |35.8 |33.4 |- |22.8 – 33.3 |

□ What are the clinical findings in hepatic failure?

▪ Jaundice, edema, ascites, hypoalbuminemia, coagulopathy, hepatic encephalopathy, Disseminated intravascular coagulation, hepatic-renal syndrome

□ What to make of this data when they’re all abnormal?

▪ AST is the most abnormal of the values, so it’s most likely that she has acute hepatocellular injury and not cholestasis.

▪ There is acute loss of liver synthetic function as well (low albumin and prolonged PT). Hence, she has acute hepatocelluar injury that has progressed to fulminant hepatic failure. These are the typical lab values you would see.

□ Low Deritis ratio.

□ In the lab, there is no measurement of indirect bilirubin; the total (TBil) and direct (Dbil) are measured and then the indirect is calculated by subtracting direct from total. TBil – DBil = IBil

▪ So, if you take the normal values and subtracted (1.3 minus 0.3), the normal IBil should be indirect

□ Low Albumin & total protein

□ High ammonia – ammonia is a toxic metabolic compound that is metabolized by the liver. The liver is suppose to get rid of ammonia, so if you are in hepatic failure, ammonia builds up. This may contribute to hepatic encephalopathy.

□ Prolonged PT & aPTT

□ Elevated Alk. Phos. & GGT – sometimes, even though hepatic failure is not mainly a cholestatic process.

← Histo slide: Centrilobular coagulative necrosis of hepatocytes.

□ See lots of red (and “red is dead”)

← Differential Dx of fulminant hepatic failure (page 442 of MINI Robbins, and he read straight from it)

□ Viral hepatitis = #1 cause worldwide (Hep. A, B, C, D, E, also Herpes virus, yellow fever, CMV)

▪ Hep B is the most likely one

▪ Hep A & E are rarely severe enough to cause fulminant hepatitis

▪ Hep B & D co-infection can do it

□ Toxins, esp. acetaminophen = #2 cause overall (also INH, CCl4, Rifampin, Halothane, mushroom toxins)

□ Vascular lesions, rarely because of dual blood supply (hepatic a. & portal v.)

▪ Budd-Chiari syndrome – blockage of hepatic vein

▪ Large Hepatic infarcts

□ Massive malignant infiltration

□ Wilson’s disease – normally more likely to lead to cirrhosis through chronic hepatic failure.

□ Microvesicular steatosis - rare

▪ Reye’s syndrome

▪ Acute fatty liver of pregnancy

□ Hyperthermia

← Which is more likely in this patient? Acute viral hepatitis and drug or toxin-induced hepatitis are good choices. Vascular diseases? Maybe. She is kind of young to have massive malignant infiltration. Reye’s, hyperthermia are not too likely. She is not pregnant.

← How do you narrow the differential dx?

□ Most important: take a good history. In this case, the patient admitted to having taken lots of Tylenol for a sore throat

□ Hepatitis serology test A-D

□ Measure serum acetaminophen levels

□ Do these first and if negative, then worry about the rest of the stuff on the differential.

← Metabolism of acetaminophen “this is not all that important for you to know right now”

Acetaminophen

gluthathione gluthathione

Acetosulfate acetoglucuronide

Mercapturic acid

□ Conjugated to sulfates or glucuronides by the liver until it runs out of glutathione. It is then converted to more toxic metabolites such as mercapturic acid, which damage hepatocytes by binding to cell membranes and proteins. Massive doses of acetaminophen deplete the glutathione stores and causes hepatic failure

□ In healthy adults, 7.5 g can cause acute hepatic failure if taken in one big dose (about 15 extra-strengthTylenol 500mg); it takes only 150 mg/kg in children.

▪ If there is an underlying liver disease, damage accomplished with a lot less Tylenol. The patient is a heavy drinker, so this may have played a role.

▪ Lower doses can accumulate over several days to result in hepatic failure. It doesn’t have to be taken all at once. The patient was taking Tylenol for several days

← Clinical presentation of acetaminophen overdose: has 4 phases assuming that you OD in one big dose.

□ Phase 1: 12-24 hours – GI irritability such as n&v

□ Phase 2: 24-72 hours – symptoms improve, but liver function tests are abnormal

□ Phase 3: 72-96 hours – acute hepatic failure

□ Phase 4: 4 days -2 weeks – resolution, if patient survives.

← Making the diagnosis

□ History is most important. She may have taken Tylenol in a suicide attempt.

▪ Don’t forget that there are a lot of medications with Tylenol as a component in addition to a narcotic (Vicodin, Lortab, Darvocet, Tylox)

□ With suspicion of Tylenol OD, you want to get a serum acetaminophen level ASAP. The longer you wait, the less information it will give you.

□ Ask when they took the Tylenol and compare the lab values with their answer using a table called the Rumack nomogram, available in most clinical reference books.

Potential for toxicity

Acetaminophen

Plasma conc.

Toxicity safety zone

unlikely

Hours post ingestion

▪ Values plotted above the pre-determined descending vertical line are representative of toxicity. Those falling below it mean that toxicity is unlikely. This doesn’t work as well if Tylenol is taken in multiple doses.

← Treatment (“Not on the test” so forgive me if I skip most of the explanation)

□ Mucomyst (N-acetylcysteine) – regenerates or acts as a substitute for glutathione. Give as early as possible (before 24 hours). Works best if taken ................
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