Acute liver disease

Terms in this set (36)

Liver Chemistry Studies
-Serum aminotransferases (transaminases)
aspartate aminotransferase (AST) (SGOT)
- alanine aminotransferase (ALT) (SGPT)
- Alkaline phosphatase Bilirubin
- Albumin
- Prothrombin time
Approach to Patient with Abnormal
Liver Chemistry Studies
Requires consideration of the following factors:
-patient's age (higher in higher age)
-symptoms
- risk factors for liver disease(overweight, fatty liver etc )
- personal or family history of liver disease concurrent medical illnesses
- medications used
- examination findings
Serum Aminotransferases
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Serum Aminotransferases
- AST - in decreasing order of concentration, found in the following:
liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes/erythrocytes
-ALT - found primarily in the liver

Pattern of aminotransferase elevation can be helpful
ALT ≥ AST in most acute hepatocellular disorders
AST:ALT ratio > 2:1 suggestive of alcoholic liver disease (AST: ALT ratio > 3:1 highly suggestive)
AST rarely > 300 U/L in alcoholic liver disease(ALT often normal)
serum ALT low in alcoholic liver disease due to deficiency of pyridoxal phosphate

-Absolute elevations of aminotransferases - no prognostic significance in acute hepatocellular disorders
-Any type of liver cell injury
modest elevations in serum aminotransferases
levels up to 300 U/L -nonspecific
Obstructive jaundice
serum aminotransferases usually NOT greatly elevated
exception - during acute phase of biliary obstruction (passage of gallstone into common bile duct), can be briefly 1,000-2,000 U/L then quickly decrease and evolve into pattern typical of cholestasis (while stone increased)
Serum Aminotransferases in Autoimmune Hepatitis
Should be considered in patients with the following:
-serum AST & ALT values > 5 times normal
-history of other autoimmune diseases
-history of hypergammaglobulinemia
-presence of positive ANA or anti-SMA
40% of patients with autoimmune hepatitis have an acute presentation (most patients have chronic disease on liver
Serum Aminotransferases in Acute Hepatitis
Serum Aminotransferases in Acute Hepatitis
Patients with acute hepatitis often have:
-fatigue, nausea, mild upper abdominal pain, & jaundice
Serum AST & ALT values are usually > 500 U/L
Virus- or drug-induced acute hepatitis usually results in AST & ALT values > 1,000 U/L (ALT > AST)
Serum ALT values > 5,000 U/L are usually due to:
acetaminophen hepatotoxicity
ischemic hepatitis ("shock liver")
unusual viruses (ex: HSV)
Serum Bilirubin
Serum bilirubin concentration measured
-direct (conjugated) fraction - water soluble, excreted in urine
-indirect (unconjugated) fraction - insoluble in water, bound to albumin in blood
Diseases associated with overproduction of bilirubin
-ex: hemolysis, resorption of a hematoma
-hyperbilirubinemia ≤ 20% conjugated bilirubin
Diseases with hepatocellular dysfunction or impaired bile flow
-hyperbilirubinemia ≥ 50% conjugated bilirubin
Serum alkaline phosphatase
Serum alkaline phosphatase isoenzymes
-liver
-bone
-placenta
-small intestine - less common
Serum alkaline phosphatase can be elevated in:
-patient over age 60 (1-1.5x normal)
-blood types O & B after fatty meal (intestinal alkaline phosphatase release into blood)
-bone alkaline phosphatase in rapid bone growth in children/adolescents
-normal pregnancy due to placenta
...
Albumin
-Synthesized exclusively in hepatocytes
-Long half-life (15-20 days)
due to slow turnover, not a good indicator of acute or mild hepatic dysfunction
Acute liver conditions
-only minimal changes in serum albumin
-if albumin < 3mg/dl, raises suspicion of chronic liver disease
PT
Prothrombin Time (PT)
Expressed as an international normalized ratio (INR)
Collectively measures factors II, V, VII, & X (shorter half-life than serum albumin)
Elevated INR may be due to:
-vitamin K deficiency (ex: antibiotic administration, prolonged fasting, small bowel mucosal disorders such as celiac disease)

Hepatocellular dysfunction
-characterized by inability to synthesize clotting factors despite adequate stores of vitamin K
Administration of vitamin K
-will improve INR within 2 days in a patient withvitamin K deficiency
-no effect in a patient with abnormal INR due to poor hepatic synthetic function
Albumin & Prothrombin Time
Markers of synthetic liver function
Abnormal albumin & prothrombin time
-imply severe hepatocellular dysfunction
-should prompt immediate evaluation ( do all enzymes INR PT etc)
Categories of Abnormal Liver Chemistry Studies
Two primary categories:
Categories of Abnormal Liver Chemistry Studies
Two primary categories:
Hepatitis
diseases characterized by hepatocellular injury
primarily results in elevations of AST & ALT
Cholestatic liver disease
primarily results in elevation of serum alkaline phosphatase
However, can have a mixed hepatocellular and cholestatic pattern in any systemic inflammatory process (such as infection or immune disorder)
Liver Chemistry Studies (continued)
Liver Chemistry Studies (continued)
Can be used to:
-detect the presence of liver disease
-distinguish among different types of liver disorders gauge the extent of known liver damage
- follow the response to treatment
Caveats:
- can be normal in patients with serious liver disease
- can be abnormal in patients with diseases that do not affect the liver
- indirect, static measurements
Acute versus Chronic Hepatitis
Acute versus Chronic Hepatitis
-Acute hepatitis
-condition lasting < 6 months
culminates in:
complete resolution of liver damage with return to normal liver function/structure OR
rapid progression of acute injury → extensive necrosis → fatal outcome
Chronic hepatitis
-sustained inflammatory process in liver > 6 months
-often impossible to differentiate from acute hepatitis on histologic criteria alone
...
Drug-Induced Liver Disease
Liver injury can occur after:
-inhalation
-oral ingestion
-parenteral administration
Two major types of chemical hepatotoxicity
-direct toxic type
-idiosyncratic type (subset of idiosyncratic - 25% hypersensitivity reactions)
rash fever eosinophil in peripheral bld smear with hypersens
Question patients carefully
-prescription drugs
-over-the-counter drugs
-herbal or alternative substances

Drug metabolism - most drugs are water- insoluble & undergo metabolic transformation to a water soluble form for renal or biliary excretion
Drug metabolism
-phase I reaction - oxidation or methylationmediated by cytochrome P450
-phase II reaction - glucuronidation or sulfation
-phase 3: inactivation by glutathione enzyme
drug induced liver disease
Direct toxic hepatitis
-occurs with predictable regularity if exposed to the offending agent
-dose-dependent
-latent period between exposure & liver injury is short (several hours)
-clinical manifestations may be delayed for 24-48 hours
-board related stuff
Drug-Induced Liver Disease (continued) - idiosyncratic
Idiosyncratic drug reactions
-usually infrequent
-usually unpredictable
-25% of reactions - hypersensitivity with extrahepatic manifestations of rash, arthralgias, fever, leukocytosis & eosinophilia
- likely caused by drug metabolites instead of intact drug
-thought to result from differences in metabolic reactivity to specific agents

Idiosyncratic drug reactions (continued)
-concept of "adaptation"
-mild, transient, nonprogessive serum aminotransferase elevations that resolve with continued drug use
-mechanism unknown
-can occur with isoniazid (INH), valproate, phenytoin, & HMG-CoA reductase inhibitors
Drug-Induced Liver Disease (continued)
Treatment
Drug-Induced Liver Disease (continued)
Treatment
-largely supportive (EXCEPT acetaminophentoxicity which has specific treatment)
-fulminant hepatitis from drug hepatotoxicity - liver transplantation may be life-saving
-withdrawal of suspected agent indicated at first sign of adverse reaction
-liver involvement should not divert attention from renal or other organ involvement threatening survival
Acetaminophen Hepatotoxicity (continued)
Acetaminophen Hepatotoxicity (continued)
"Therapeutic misadventure"
- in setting of severe febrile illness
- several days of anorexia and near-fasting
- regular administration of extra-strength acetaminophen
- results in combination glutathione depletion and relatively high NAPQI levels
Acetaminophen Hepatotoxicity - Treatment
Acetaminophen Hepatotoxicity - Treatment
Treatment of acetaminophen overdosage
-gastric lavage
-supportive measures
-oral activated charcoal or cholestyramine (not typically effective if given > 30 minutes after overdose)
-check risk of hepatotoxicity from nomogram plot of acetaminophen plasma levels versus hours after ingestion

Administration of sulfhydryl compounds (ex: cysteamine, cysteine, N-acetylcysteine) reduces severity of hepatic necrosis
-given if acetaminophen blood levels > 200μg/ml at 4 hours or > 100μg/ml at 8 hours
-should be given within 8 hours of ingestion
-may be effective even as late as 24-36 hours-
- sulfhydryl groups bind toxic metabolite & stimulate synthesis of hepatic glutathione
- Liver transplant
Algorithim Drug induced
Algorithim Drug induced
>5 times ULN - stom drug
<3 repeat enzymes 1-3 months
3-5 repeat enzymes 2-4weeks
in real life just stop it

Acetaminophen
Statin
Diclofenac
Minocycline
Augmentin
Amoxicillin
Erythomyocin
Amiodarone
Acetaminophen Hepatotoxicity
Acetaminophen Hepatotoxicity
- Severe centrilobular hepatic necrosis when ingested in large doses
-Single dose of 10-15 gm may produce clinical evidence of liver injury
-Fatal fulminant disease usually (not always) associated with ingestion ≥ 25 gm
-Blood levels of acetaminophen correlate with severity of hepatic injury
blood levels > 300μg/ml - 4 hours after ingestion predictive of severe damage
blood levels < 150μg/ml - 4 hours after ingestion highly unlikely to result in injury
-diff amounts for alcoholics can cause problems
Acetiminophen again
-Early manifestations 4-12 hours after ingestion:
nausea & vomiting, diarrhea, abdominal pain, shock
-Hepatic injury - becomes apparent 24-48 hours after acute symptoms resolve
-Maximal abnormalities & hepatic failure may not be evident for 4-6 days
-Aminotransferase levels approaching 10,000 U/L are not uncommon
-Renal failure & myocardial injury may be concomitant
Acetaminophen metabolism
Acetaminophen Hepatotoxicity (continued)
Acetaminophen metabolism
-predominantly phase II metabolism to innocuoussulfate & glucuronide metabolites
-small proportion metabolized by phase I reaction to hepatotoxic metabolite by cytochrome P450 2E1
-toxic metabolite = N-acetyl-benzoquinone-imide (NAPQI) (responsible for the damage) - detoxified by binding to hepatoprotective glutathione

NAPQI covalent binding to nucleophilic hepatocyte macromolecules leads to hepatocyte necrosis if:
-excessive amounts of NAPQI formed
-glutathione levels low
-glutathione levels depleted or overwhelmed
Acetaminophen Hepatotoxicity (continued)
Hepatic injury potentiated by:
Acetaminophen Hepatotoxicity (continued)
Hepatic injury potentiated by:
-prior administration of alcohol
alcohol induces cytochrome P450 2E1 - increased levels of NAPQI produced
alcohol suppresses hepatic glutathione production
chronic alcoholics - toxic dose of acetaminophen may be as low as 2gm
- prior administration of phenobarbital
-starvation (reduces hepatic glutathione)
- conditions which stimulate the mixed-function oxidase system
Toxin-Induced Liver Disease
Toxin-Induced Liver Disease
Generally cause direct toxic hepatitis
Industrial toxins
-carbon tetrachloride - centrilobular zonal necrosis
- trichloroethylene - centrilobular zonal necrosis
- yellow phosphorus - periportal injury
Hepatotoxic mushroom poisoning
-heat-stable toxic bicyclic octapeptides
-species - Amanita phalloides & Galerina
-produce massive hepatic necrosis
-lethal dose - 10mg, the amount in a single deathcap mushroom

Herbal, complementary, & "alternative" medicines
- scientifically unproven efficacy of these substances
-lack prospective safety oversight
- megadoses of vitamin A can cause liver injury
-some Chinese herbal teas contaminated with pyrrolizidine alkaloids - cause liver injury
-examples of herbal remedies associated with hepatic injury: germander, chaparral, comfrey, Ma Huang, valerian root
...
Alcohol-Induced Liver Disease
Chronic & excessive alcohol ingestion - major cause of liver disease in the Western world
Pathology of alcoholic liver injury - 3 major lesions (rarely pure):
- fatty liver - present in > 90% of binge and chronic drinkers
- alcoholic hepatitis - small % progress
- cirrhosis - prognosis dismal
Quantity & duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver
Risk factors for alcoholic liver disease
Risk factors for alcoholic liver disease
Quantity
-in men, 40-80 gm/day of ethanol produces fatty liver; 160 gm/day for 10-20 years causes hepatitis or cirrhosis; 15% of alcoholics develop cirrhosis
-12 grams of alcohol
8 ounces beer
4 ounces wine
1 ounce 80% spirits
Gender
-in women, increased susceptibility > 20 gm/day

-Hepatitis C
-concurrent infection with alcoholic liver disease - associated with increased severity at younger age, more advanced histology, decreased survival
Genetics
-gene polymorphisms - alcohol dehydrogenase &cytochrome P450 2E1 (chinese and Asians have decreased)
Malnutrition/nutrition
-not required for alcohol injury
-concurrent obesity & fatty liver increase risk
Alcohol-Induced Liver Disease (continued)
Clinical features
Alcohol-Induced Liver Disease (continued)
Clinical features
-alcoholic fatty liver - subtle, hepatomegaly oftenthe only finding
-occasionally fatty liver will present with RUQ pain, tender hepatomegaly, nausea, jaundice
-fever, spider nevi, jaundice, abdominal pain simulating acute abdomen, features of portal hypertension - extreme end of spectrum
Alcohol-Induced Liver Disease (continued)
Laboratory features
Alcohol-Induced Liver Disease (continued)
Laboratory features
- AST:ALT ratio > 2:1 suggestive of alcoholic liver disease (AST: ALT ratio > 3:1 highly suggestive)
- AST rarely > 300 U/L in alcoholic liver disease (ALT often normal)
- serum ALT low in alcoholic liver disease due to deficiency of pyridoxal phosphate
- hyperbilirubinemia common
- modest increases in alkaline phosphatase
Alcohol-Induced Liver Disease (continued)
Treatment
-complete abstinence from alcohol - cornerstone
-alcohol counseling or treatment programs
-nutritional counseling
-pyschosocial therapy
- Discriminant Function (DF) >32 - glucocorticoids versus pentoxifylline
DF = 4.6 x (PT patient - PT control) + serum bilirubin (mg/dl)
DF score > 32 = 50% mortality in 30 days! **** (give them prednisone/hopefulyy theu can live long enough for transplant
- liver transplant - only if sobriety > 6 months
alcohol-Induced Liver Disease (continued)
Prognosis
- short-term mortality in critically ill - 70%
-severe alcoholic hepatitis
coagulopathy (PT > 5 sec)
anemia -due to bleeding
serum albumin < 2.5mg/dl
serum bilirubin levels > 8mg/dl renal failure
ascites - dismal
variceal hemorrhage - dismal
deep encephalopathy - dismal
hepatorenal syndrome - dismal -liver failure and kidney problem
-no alcoholic patients can get transplant unless sober in program for 6 months
Reyes syndrome
Reye's Syndrome (continued)
-Acute illness encountered exclusively in children < 15 years of age
-Onset usually follows an URI or viral illness (particularly influenza or chicken pox)
-Within 1-3 days, persistent vomiting
-Signs of stupor & progressive central nervous systemdamage - progresses to seizures & coma
-Signs of hepatic injury - liver is enlarged, but jaundice absent or minimal
- Cause - unknown; viral illness & salicylates implicated
- Decreasing incidence - likely due to increased recognition & decreased aspirin use in this clinical situation

Major laboratory findings
-elevations in transaminases, prothrombin time & ammonia hypoglycemia
- metabolic acidosis
- extensive fatty vacuolization of liver & renal tubules
- mitochondrial dysfunction
Mortality rate = 50%
Treatment
-infusions of 20% glucose
-fresh-frozen plasma
-intravenous mannitol (reduce cerebral edema)
HELLP
HELLP Syndrome
Condition unique to pregnancy
- hemolysis (H)
microangiopathic hemolytic anemia
abnormal peripheral smear, low serum haptaglobin, elevated indirect bilirubin, elevated LDH
-elevated liver (EL) function tests
serum AST > 2x upper limit of normal
-low platelet (LP) count
< 100,000/μL

Initial symptoms
-vague, nausea, vomiting, viral-like syndrome, headaches, vision changes
- right upper quadrant pain
Unrecognized - major morbidity & mortality
Treatment
- high-risk obstetric center
- cardiovascular/hemodynamic stabilization correction of coagulation abnormalities
- prompt delivery
ischemic hep
Ischemic Hepatitis Ischemic hepatitis = "shock liver"
-Hepatic blood supply
portal vein - 2/3
hepatic artery - 1/3
- Most patients have circulatory shock from cardiovascular disease, sepsis, or profound hypovolemia leading to complication of ischemic hepatitis
- Hours to days after insult - serum transaminases, lactate dehydrogenase, & bilirubin increase to variable degrees
Treatment Ischemic Hepatitis (continued)
Severe injury
- serum transaminases in the several thousands
- marked prolongation of prothrombin time
treatment
-largely supportive
-optimize systemic hemodynamics
- infections/sepsis - broad-spectrum antibiotics
-most lab abnormalities improve in 1-2 weeks (rapid declines in AST & ALT in 24-48 hours)
- if patient survives, liver function usually returns to normal
- overall prognosis - poor due to underlying critical illness
Granulomatous Liver Disease
- Liver infiltrated with granulomas may be slightly enlarged & firm
- Hepatic dysfunction is usually limited
- Increases in serum alkaline phosphatase -
common (mild to marked)
- Occasionally & less commonly, mild elevations of serum transaminases
- Needle biopsy of liver - often provides first definite evidence of systemic or disseminated granulomatous disease

Granulomatous Liver Disease (continued)
Systemic Disease
- sarcoidosis - portal hypertension may develop Hodgkin's & non-Hodgkin's lymphoma
- primary biliary cirrhosis
- Crohn's disease
- Wegener's granulomatosis
- idiopathic granulomatous hepatitis
Infections - Bacterial
-mycobacterial disease - tuberculosis, M. Avium
- brucellosis - portal hypertension may develop
- leprosy

Granulomatous Liver Disease (continued)
Infections - Viral
-Epstein-Barr virus (EBV)
-Cytomegalovirus (CMV)
-chicken pox
Infections - Rickettsial
Q fever
Infections - Parasitic
schistosomiasis - extensive necrosis with scarring may occur
Infections - Spirochetes
- syphilis
Drugs
- sulfonamides
-isoniazid (INH)
- allopurinol
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