16. Liver function tests
General considerations
 See American Gastroenterology Association technical review on liver function tests in Gastroenterology
2002;123:1367.
 If asymptomatic, repeat to confirm; if still abnormal, decide which pattern LFT abnormalities fit into:
 Hepatocellular, elevated transaminases with normal-mildly elevated alk phos and normal to elevated
bilirubin
 Cholestatic, elevated alk phos and bilirubin with normal to mild elevations in aminotransferases
 Mixed picture and infiltrative
Hepatocellular pattern, etiologies
Causes of chronically elevated
 AST (SGOT) can be found in, in decreasing order: liver, cardiac
transaminases
Hepatic causes
muscle, skeletal muscle, kidney, brain, pancreas, lungs, leukocytes,
Alcohol abuse
and erythrocytes
Medication
 ALT (SGPT) much more specific to liver
Chronic hepatitis B and C
 Causes of acute transaminitis
Steatosis and nonalcoholic
steatohepatitis
 Acute viral hepatitis (A, B, C, D, E)
Autoimmune hepatitis
 Toxin or drug (e.g. acetaminophen)
Wilson’s disease (in patients <40)
 Ischemic (e.g. shock liver)
Alpha1-antitrypsin deficiency
Non hepatic causes
 In critical illness, transaminitis usually multifactorial from
Celiac sprue
intrahepatic cholestasis secondary to sepsis, hepatic congestion
Inherited disorders of muscle
from CHF, and/or medications
metabolism
 Degree of aminotransferase elevation does not correlate with
Acquired muscle diseases
Strenuous exercise
hepatocyte necrosis
From N Engl J Med 2000;342:1266
 Alcoholic liver disease:
 AST:ALT > 2 because of relative deficiency of ALT given
alcohol-related deficiency of pyridoxal-6-phosphate, required for
Drugs associated with liver
ALT activity
injury
 AST can be elevated up to 8x normal
Hepatitis-like injury
 ALT could be normal to 5x normal
Acetaminophen
 Hepatic steatosis and NASH
Alpha-methyldopa
 Associated with increased body mass index, diabetes, and
Diclofenac and other NSAIDs
Glyburide
hypercholesterolemia
Isoniazid
 Can progress to cirrhosis
Methorexate
 AST and ALT < 4x normal and AST:ALT < 1; alk phos normal
Niacin
or up to 2x normal; usually asymptomatic; can be evaluated by
Nitrofurantoin
Statin drugs
RUQ ultrasound and then liver biopsy
Cholestasis
 Hereditary hemochromatosis
Amoxicillin/clavulanate
 Initial test Fe and TIBC
Androgens
 Ff Fe/TIBC > 45%, check ferritin
Captopril
Chlorpromazine
 Ferritin > 400 ng/ml in men and > 300 ng/ml in women
Erythromycin
suggestive; then send for HFE genotype
Estrogens (oral contraceptives)
 Hepatic iron index (ratio of liver concentration of iron to age of
Parenteral nutrition
patient) > 2.0 is diagnostic
Tolazamide
Tolbutamide
 Autoimmune hepatitis
Trimethoprim-sulfamethoxazole
 Screen with SPEP; 80% patients will have
hypergammaglobulinemia (2x upper limit of normal is specific)
 Check ANA (>1:160, especially in homogeneous pattern) and anti-smooth muscle antibody
MGH Medical Housestaff Manual
50
16. Liver function tests
 Liver biopsy for definitive diagnosis
 Wilson’s disease
 Most patients <40
 Screening test is serum ceruloplasmin; suggestive if low (<200mg/L) or presence of Kayser-Fleischer
rings or 24-hr urine copper >100 mcg/d
 Definitive diagnosis by liver biopsy showing >250 mcg Cu/g liver
 Celiac sprue
 Suspect if weight loss, malabsorptive diarrhea, arthritis, vague abdominal pain
 Screen with antiendomysial IgA (most sensitive and specific) and/or antigliadin IgA and IgG
 Alpha1-AT deficiency
 If SPEP shows low alpha globulin levels, send for serum AT levels (<80 mg/dL suggestive) and PiZZ
phenotyping
ALT and AST >15X upper
 Ischemic hepatitis
limit of normal
 Rapid rise in AST and ALT in 24 hrs but rapid resolution in 2-6 days
 Acute viral hepatitis (A-E,
 Mild bilirubin elevation (<4x normal); alk phos < 2x normal
Transaminitis, evaluation
herpes)
Medications/toxins
Ischemic hepatitis
Autoimmune hepatitis
Wilson’s disease
Acute bile duct obstruction
Acute Budd-Chiari
syndrome
 Hepatic artery ligation






 Degree of AST and ALT elevation and AST:ALT ratio
 AST:ALT > 2 and AST < 300 IU/L suggest alcoholic hepatitis
 AST:ALT ratio 1 in fatty liver disease or acute or chronic viral
hepatitis
 AST:ALT >1 can be seen in cirrhosis from any cause
 AST:ALT >4 is highly suggestive of fulminant Wilson’s hepatitis
 AST and ALT levels of >15X upper limit normal, see table
 If not clearly medication- or alcohol-induced liver disease, initial tests include hep B sAg, hep B sAb, hep B
cAb, hep C Ab, hep A IgM and IgG (if clinically indicated), Fe/TIBC, ceruloplasmin (if age < 40), SPEP
(assess for autoimmune hepatitis and alpha1-antitrypsin deficiency), TSH
 If hypergammaglobulinemia on SPEP, check ANA and anti-smooth muscle Ab to assess for autoimmune
hepatitis; will need liver biopsy for definitive diagnosis
 If alpha-globulin band low on SPEP, check alpha1-antitrypsin level
 If Fe/TIBC > 45%, high suspicion of hemochromatosis, send for ferritin.
 If ferritin high, check genotype of HFE and liver biopsy; hepatic iron index of >1.9 on liver biopsy c/w
homozygous HFE
 If suspicion of Wilson’s high (e.g. neurologic symptoms, age <40), and ceruloplasmin level not
decreased, check for Kayser-Fleischer rings; if still negative, check 24-hr urine for copper excretion
(>100 mcg/d is suggestive)
 If all the above negative, check abdominal ultrasound to assess for fatty infiltration into the liver to suggest
hepatic steatosis or NASH; definitive diagnosis requires liver biopsy
 Additional tests if initial ones are negative to evaluate for nonhepatic source of transaminases
 Antiendomysial and antigliadin Abs to look for celiac sprue, CK to look for muscle disease
 Consider liver biopsy if no clear diagnosis
Cholestatic pattern
 Causes include biliary obstruction (stones, cancer, stricture), PBC, PSC, intrahepatic cholestasis of sepsis,
medications, infiltrative disease
 Alkaline phosphatase present in liver, bone, intestine, kidney, placenta, leukocytes, small intestine, and
neoplasms
MGH Medical Housestaff Manual
51
16. Liver function tests
 Rise of alk phos up to 3x normal nonspecific; striking elevation seen in infiltrative processes (primary or
metastatic tumor) or biliary obstruction (intra- or extrahepatic)
 5 nucleotidase found in liver, cardiac muscle, brain, blood vessels, and pancreas but significant elevation of
serum levels almost exclusively seen in liver disease; may take
Infiltrating diseases of the liver that
several days for elevated levels to be detected; sensitivity
can cause elevated serum alk phos
comparable to that of AP in detecting biliary obstruction, hepatic
 Sarcoidosis
infiltration, and cholestasis
 Tuberculosis
 Primary biliary cirrhosis
 Fungal infection (e.g.
 Seen in women in their 50-60s, especially those with
coccidiodomycosis, histoplasmosis)
hypercholesterolemia
 Other granulomatous diseases
 Bilirubin normal initially
 Amyloidosis
 AMA IgM highly suggestive of PBC
 Lymphoma
 Definitive diagnosis by liver biopsy
 Metastatic malignancy
 Primary sclerosing cholangitis
 Hepatocellular carcinoma
 Affects men in their 30-40s
 History of inflammatory bowel disease (especially UC)
suggestive
 Diagnosis by ERCP and/or liver biopsy
Isolated hyperbilirubinemia
 Infiltrative diseases (see box)
Cholestatic pattern, evaluation
 Confirm hepatic origin of elevated alkaline
phosphatase with 5 nucleotidase (more commonly
performed at MGH than GGT)
 Right upper quadrant ultrasound to assess for
cholestasis or infiltrative disease
 If U/S negative, check anti-mitochondrial Ab (good
sensitivity and specificity) to evaluate for primary
biliary cirrhosis
 If positive, consider liver biopsy
 If both RUQ U/S and anti-mitochondrial Ab negative
 Consider liver biopsy and/or ERCP if alk phos >
50% above normal (ERCP can assess for PSC;
liver biopsy may miss it)
 Indirect hyperbilirubinemia, >85% of total
bilirubin is unconjugated
 Total bilirubin usually never >6 mg/dL in
hemolysis
 Check reticulocyte count and hemolysis labs
 Direct hyperbilibinemia, >50% of total bilirubin
is conjugated
Causes of indirect hyperbilirubinemia
Hemolysis
Ineffective erythropoiesis
Resorption of large hematoma
Crigler-Najjar syndrome
Gilbert’s syndrome (bilirubin usually <3)
Shunt hyperbilirubinemia
Hepatic causes of direct hyperbilirubinemia
Bile duct obstruction
Hepatitis
Cirrhosis
Medications/toxins
Primary biliary cirrhosis
Primary sclerosing cholangitis
Sepsis
Total parenteral nutrition
Vanishing bile duct syndromes
Dubin-Johnson Syndrome
Rotor’s Syndrome
Deanna Nguyen, M.D.
MGH Medical Housestaff Manual
52
17. Pancreatitis
Background
 Pancreatitis is a common reason for admission for
management of pain and emesis/dehydration and for
management of complications.
 Complications include (see below):
 Pseudocyst formation
 Pancreatic necrosis
 Abscess formation
 Chronic pancreatitis (and possible pancreatic cancer)
with chronic pain and exocrine insufficiency.
Points to consider in the history
 Time frame of symptoms (nausea and vomiting,
abdominal pain radiating to back, pain may be relieved
while sitting up/forward and may worsen with food)
 Travel history
 History of and risk factors for dyslipidemia (DM,
hypothyroidism) or hypercalcemia (e.g.,
hyperparathyroidism)
 Good medication and alcohol history
 History of biliary colic or known risk factors of
cholelithiasis
Helpful studies and laboratory information
Etiologies
Alcohol and gallstones are the most common
two causes comprising 75% of cases
Ampullary obstruction (diverticula, tumor,
worms, foreign body)
Hypertryglyceridemia (>1000 mg/dL and
accounts for <4% of cases)
Hypercalcemia (<2% pts with
hyperparathyroidism)
Drugs (ddI, tetracyclines, sulfa agents,
furosemide, valproic acid, tamoxifen,
pentamidine, azathioprine, metronidazole,
mercaptopurine)
Infections (mumps, EBV, HIV, CMV, HSV,
ascariasis, coxsackie, viral hepatitis)
Vascular causes (vasculitis, ischemia,
atherosclerotic emboli)
Trauma (blunt)
Iatrogenic (post-ERCP, post-abdominal
surgery)
Toxins (scorpion venom, organophosphorous
insectisides, methyl alcohol)
Pregnancy (multifactorial)
Idiopathic (10%)
 Serum amylase: increases 2-3 hrs after attack and stays
high for 3-4 days
 No correlation between peak level and severity
 Non-pancreatic causes of elevation are renal failure,
viscus perforation/infarct, ectopic pregnancy, cancer,
macroamylassemia
 Serum lipase: more sensitive and specific and remains elevated longer than amylase
 Serum calcium, lipids, LDH, CBC, albumin, glucose, liver chemistries
 RUQ ultrasound to evaluate biliary tree for obstruction/cholelithiasis
 CXR may show pleural effusion or ARDS
 CT scan with contrast to evaluate for necrosis or presence of pseudocyst or abscess (evaluate for necrosis after
1 week). Consider CT scan in patients who are deteriorating or who have severe pancreatitis, i.e. not all
patients require CT scan.
 Note that controversy exists whether or not ionic contrast may worsen pancreatitis.
 ERCP ± sphincterotomy in setting of biliary obstruction
Complications
 Pseudocyst. Non-epithelial lined cavity often presenting with persistent pain and hyperamylasemia. 50-80%
resolve within 6 weeks
 Pancreatic abscess. Develops within 2-4 weeks, often presenting with fever, pain, and persistent
hyperamylasemia
 100% mortality if not drained; affects 30% pts with severe acute pancreatitis.
 E. coli, Pseudomonas, Klebsiella, and Enterococcus spp are most common; 75% are monomicrobial
MGH Medical Housestaff Manual
53
17. Pancreatitis




Systemic inflammatory response syndrome
Pancreatic ascites and pleural effusion (left>right)
Metastatic fat necrosis/panniculitis
Chronic pancreatitis
Main goals and mainstays of treatment
 Reversal of precipitants
 Early ERCP in patients with gallstone pancreatitis who have obstructive jaundice (bilirubin >5) or biliary
sepsis
 Treatment of hypercalcemia
 Cessation of possible causative drugs
 Mild pancreatitis is treated for several days with supportive care consisting of analgesia, IVF, and NPO.
 Consider nasogastric tube for ileus or vomiting.
 Role of antibiotic prophylaxis (in absence of necrosis) is controversial. Studies have shown decreased
frequency of sepsis but no different in mortality rate with imipenem.
 Surgery is indicated only when necrotizing pancreatitis is infected.
 Acute necrotizing pancreatitis (involving more than 30% of pancreas) generally warrants broad spectrum
antibiotics (e.g. imipenem or meropenem).
 Enteral feeding via nasojejunostomy tube should be attempted with high protein/low fat preparations if pts are
NPO for more than 7-10 days. Consider TPN in patients who do not tolerate enteral feeding.
 Oral refeeding when abdominal pain and tenderness resolve and there is no complication. Begin with liquids.
Deanna Nguyen, M.D.
MGH Medical Housestaff Manual
54
18. Acute liver failure
Background
 Severe acute hepatitis = jaundice and coagulopathy without hepatic encephalopathy
 Fulminant hepatic failure, as defined by Trey and Davidson initially = severe acute hepatitis + hepatic
encephalopathy within 8 weeks of onset of jaundice without previous existing liver disease
 More recently, ALF defined as fulminant hepatic failure if hepatic encephalopathy develops within 2 weeks
after onset of jaundice and as subfulminant hepatitis if encephalopathy develops in 2-12 weeks.
Etiologies
 Multiple etiologies have been demonstrated to cause acute liver failure.
 Data from NIH ALF Study of 206 patients identified these as etiologies:




Acetaminophen
Indeterminate
Drug reaction (INH, rifampin, PTU, amiodarone)
Viral hepatitis (0.2-0.4% of hep A, 1.0-1.2% of hep B)





Autoimmune
Ischemic (Budd-Chiari, shock, veno-occlusive disease)
Wilson’s
Pregnancy (acute fatty liver of pregnancy, HELLP)
Malignancy (lymphoma most common)
 Other
38%
18%
14%
12%
19%
 Other etiologies have been described: carbon tetrachloride, Amanita phalloides mushrooms, NSAIDs,
halothane, Ecstasy, HDV, HEV in pregnant women in their third trimesters, valproic acid, tetracycline,
Reye’s syndrome
Complications
 Main complications are:
 Cerebral edema (develops in 80% of pts with grade 3-4 encephalopathy, due to increased permeability of BBB),
most common cause of death.
 Renal failure
King’s College Criteria
 Bacterial infection
 Additional complications include:
 Hemodynamic instability (high cardiac output but low peripheral
resistance), hemorrhage, hypoglycemia, pulmonary edema,
respiratory alkalosis, hyponatremia, hypophosphatemia,
pancreatitis
Prognostic tools
 King’s College Criteria for need for liver transplantation (most
often used); see box
 APACHE II score (worse if >15 in acetaminophen group, >13
in non-acetaminophen)
 Serum AFP (increase in AFP from day 1 to day 3 had a 83%
sensitivity and 68% specificity for predicting outcome)
 Clichy criteria
 Hepatic encephalopathy (grade III-IV) and factor V level <20% in
pts <30 y.o. or <30% in pts >30 y.o. are associated with low
likelihood of spontaneous recovery
Acetaminophen
 Arterial pH <7.3 (irrespective of grade
of encephalopathy) OR
 Grade III/IV encephalopathy AND PT
>100 s AND creatinine >3.4
All other causes
 PT >100 s (irrespective of grade of
encephalopathy) OR
Any three of the following
 Age <10 or >40
 Etiology: non-A, non-B hepatitis,
halothane hepatitis, idiosyncratic
 Duration of jaundice before onset of
encephalopathy >7 days
 PT >50 s
 Bilirubin >18 mg/dL
 Admission encephalopathy grade and bilirubin level have been noted to be independent predictors of
spontaneous survival.
MGH Medical Housestaff Manual
55
18. Acute liver failure
 Specifically, a mean total bilirubin of 6 among survivors and 17 among non-survivors. Also 65-70% survival in
patients with grade I-II encephalopathy compared to <20% survival in patients with grade IV encephalopathy.
 Liver pathology: >70% necrosis associated with 90% mortality rate without transplantation
 MELD scale. Model End Stage Liver Disease. New model for scoring severity (calculator also available on
Palm software MedCalc).
 Score = 9.57  ln (creatinine) + 3.78  ln (total bilirubin) + 11.2  ln (INR) + 6.43
where creatinine, bilirubin, and INR > 1, creatinine <4, maximum MELD score is 40
 In acute liver failure from acetaminophen toxicity, arterial lactate >3.5 mmol/L had good predictive value
 Early after admission (median 4 h), 67% sens, 95% specific for death; after fluid resuscitation (median 12 h), arterial
lactate >3.5 mmol/L 76% sens, 97% spec (Lancet 2002;359:558).
Main goals and mainstays of treatment
 Airway and hemodynamic stabilization of patient
 Refer (to GI liver fellow) for possible transplantation evaluation
 Look for potentially reversible cause.
 Acetaminophen (N-acetylcysteine), Amanita poisoning (consider high dose penicillin and parenteral silibinin),
Budd-Chiari (surgery), acute fatty liver of pregnancy (delivery), autoimmune (steroids +/- cytotoxic agents).
 N-acetylcysteine most helpful when given within 12 hours of acetaminophen ingestion but should be given to
all patients with acetaminophen toxicity; consider it even for non-acetaminophen ALF since there is some
evidence to suggest efficacy
 For hepatic encephalopathy, consider lactulose; avoid benzodiazepenes due to upregulation of GABA
receptors
 Supportive therapy for cerebral edema (often the mode of death):
 ICP monitoring to maintain cerebral perfusion pressure >50 mm Hg, mannitol for elevated ICP in pts without renal
failure (elevation of head of bed, hyperventilation, steroids probably not useful)
 Frequent monitoring of glucose given possible impaired hepatic gluconeogenesis and glycogenolysis,
dextrose drips for hypoglycemia
 FFP, platelets only if evidence of bleeding
 Vasopressors to support organ perfusion
 Serial blood cultures q48 hrs and low threshold for broad spectrum antibiotics since ALF pts may not mount
elevated WBC or fever due to impaired immune system
 If dialysis necessary, CVVH better than HD to avoid rapid fluid shifts
 Transplantation remains best therapy with survival of about 50-90% but organ supply and high acute
mortality from sepsis and cerebral herniation remain as obstacles. Most recent data show that only 29% are
transplanted.
 On the horizon:
 Molecular Adsorbent Recycling System (MARS), hemodiafiltration against albumin able to remove low molecular
weight toxins
 Extracorporeal liver assist devices as a bridge to transplantation and to possibly, spontaneous recovery (uses pig or
human hepatocytes)
Survival data
 Overall survival = 60%; outcomes are best for acetaminophen (65% overall survival) and worst if
idiosyncratic drug reaction or indeterminate cause (14% and 11% survival, respectively)
 High mortality rate from cerebral edema, renal failure, sepsis, multisystem organ failure
Deanna Nguyen, M.D.
MGH Medical Housestaff Manual
56
19. Acetaminophen toxicity
Toxic dose
 Minimal toxic single dose, 7.5 to 10 g for an adult.
 Toxicity likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24hour period.
 Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity.
Pathophysiology
 Route. Oral ingestion, peak serum levels can occur within 30-60 minutes but can take up to 4 hours
depending on the rate of gastric emptying. The serum half-life is 2-3 hours and is not affected by renal
clearance.
 Mechanism. Acetaminophen is primarily cleared by the liver metabolism. The majority (95%) of
acetaminophen is converted to glucuronidated or sulfonated metabolites that are inactive and non-toxic.
 5% of acetaminophen is converted by hepatic P450 enzymes to N-acetyl-p-benzoquinoneimine (NAPQI), a
highly reactive species. NAPQI is further conjugated to glutathione to produce an inactive metabolite.
 In overdose, the sulfonation and glucuronidation pathways are saturated and more drug is shunted to P450
pathways to produce NAPQI. Increased levels of NAPQI rapidly deplete glutathione stores.
 Once glutathione stores are exhausted, NAPQI reacts with cellular components resulting in hepatocyte
necrosis.
 Modifying factors. Alcoholism, pre-existing liver disease, and medications that induce microsomal P450
enzymes may all augment hepatotoxicity in acetaminophen use.
Clinical manifestations
Stage I. Initial 24 hours post ingestion
Anorexia, nausea, vomiting, diaphoresis, and malaise
Stage II. 24-48 hours post ingestion
Improved symptoms,  right upper quadrant pain, elevation of
liver enzymes (transaminases), LDH, bilirubins and increased
PT.
Stage III. 72-96 hours post ingestion
Hepatic enzymes peak. Develop sequelae of hepatic failure
including jaundice, coagulopathy, and encephalopathy.
Renal failure and myocarditis may occur. Death can result
Complete resolution and recovery
Stage IV. >4-14 days
Emerg Med Clin North Am 1984; 2:103-119
Diagnosis
 History of ingestion, stage I symptoms (see above), evidence of unexplained hepatic failure
 Key information includes amount of drug ingested and time elapsed from ingestion
 Serum acetaminophen levels—draw at  4 hours post ingestion (level of drug peaks at 4 hours), refer to
nomogram—use serum level and time elapsed since ingestion to determine toxicity risk
Management




Gastric decontamination. Gastric lavage if ingestion <4 hours to presentation
Activated charcoal. 50-100 g, adsorbs drug, most effective if given <4 hrs, but may help >4hrs
N-acetylcysteine. Replenishes glutathione stores. Can be given with charcoal without loss of efficacy.
Initial dose of N-acetylcysteine. 140 mg/kg po or nasogastric tube, draw serum acetaminophen level at 4
hrs post ingestion
MGH Medical Housestaff Manual
57
19. Acetaminophen toxicity

Subsequent therapy. If the serum level is toxic per nomogram, then admit patient and administer 17 doses of
70 mg/kg N-acetylcysteine po or nasogastric tube q4h over the next 72 hours.
 Draw LFTs (AST, ALT, bilirubin), LDH, and PT for a baseline, follow daily for 72 hours. Also consider
checking lactic acid (see acute liver failure section).
 See acute liver failure section for prognostic indicators.
nomogram adapted from Harrison’s
Principles in Internal Medicine
Hours after acetaminophen ingestion
MGH units
(mg/L)
Ravi Joshi, M.D.
MGH Medical Housestaff Manual
58
20. End stage liver disease, complications
General considerations
 Liver biopsy is gold standard for diagnosis of
cirrhosis
 RUQ ultrasound to look for ascites, vascular
patency, echogenicity/morphology of liver, biliary
tree, hepatocellular carcinoma
 Serum AFP (for HCC)
 Hyponatremia (volume overloaded), anemia
(multifactorial), thrombocytopenia (hypersplenism
and thrombopoieten deficiency)
Ascites
Modified Child-Turcotte-Pugh score
Parameter
1. Ascites
2. Total bilirubin
3. Prothrombin time
Sec over control
INR
4. Albumin
5. Encephalopathy
CTP score
5-6
7-9
10-15
1 point
none
<2
2 points
slight
2-3
3 points
moderate or worse
>3
1-3
<1.7
>3.5
none
4-6
1.8-2.3
2.8-3.4
1-2
>6
>2.3
<2.7
3-4
CTP class
A
B
C
1 yr survival
100%
80%
45%
2 yr survival
85%
60%
35%
 Most common complication of cirrhosis
 50% develop ascites within 10 years
 Multifactorial etiologies leading to avid Na retention by the kidney and transudation across the peritoneum, as
well as hypoalbuminemia, and increased hepatic lymph production
 Differential diagnosis includes portal hypertension (cirrhosis, cardiac, hepatic vein obstruction, portal
vein/splenic vein obstruction, schistosomiasis) vs. non-portal hypertension (malignancy, pancreatitis,
nephrogenic, infectious (TB), chylous, biliary
 Diagnostic tap: cell count with differential, albumin, total protein, amylase, triglycerides, gram stain, culture
(in blood culture bottles at bedside), cytology
 SAAG = serum albumin  ascites albumin gradient.
 SAAG >1.1, 97% accurate for portal HTN
 Sodium restriction is paramount (<90 mEq/day)
 Fluid restriction to <1500 mL/day (<1000 mL/day if serum Na <120 mEq/L)
 Diuretics
 UNa>30 mEq/L: spironolactone 100 mg po qd alone
 UNa 10-30 mEq/L: furosemide 40 mg po qd and spironolactone 100 mg po qd
 UNa < 10 mEq/L: furosemide and spironolactone (40:100 ratio), sodium/fluid restriction, and large
volume paracentesis
 Paracentesis, indicated in tense ascites and/or refractory ascites with low UNa
 TIPS as a bridge to transplantation if ascites refractory
Spontaneous bacterial peritonitis (SBP)
 Risk factors: low ascites total protein (<1.0)
 Must be ruled out in all cirrhotics who are admitted since its presentation ranges from asymptomatic state to
sepsis; 10-30% hospitalized cirrhotics have SBP
 Diagnose with paracentesis; three categories:
 Culture positive/neutrocytic (>250 PMN/cc), most common
 Culture negative/neutrocytic >250 PMN/cc,
 Culture positive/non-neutrocytic (<250 PMN/cc)
 Bacteriology: E. coli > Klebsiella > Strep pneumoniae > other gram negative rods. Anaerobes are rare (<5%)
 Treat with cefotaxime (or equivalent) 2 gm IV q8h x 5 days
 Some repeat paracentesis at day 3 to show cell count decline
 Albumin infusions (1.5 gm/kg on day 1 and 1.0 gm/kg on day 3) have been shown to improve mortality
when given with antibiotics potentially by preserving renal function through volume expansion (N Engl J
Med 1999;341:403)
MGH Medical Housestaff Manual
59
20. End stage liver disease, complications
 Consider prophylaxis with quinolone since 60% will recur within 1 yr
Secondary peritonitis
 If ascitic fluid is neutrocytic, and has 2 out of 3 of following: total protein > 1g/dL, glucose <50 mg/dL, LDH
>nl for serum.
 Must exclude bowel perforation or intra abdominal abscess.
 Treat with metronidazole and cefotaxime; consider emergency surgery.
Esophageal variceal bleeding








Requires hepatic venous-wedge gradient of >12 mm Hg to occur.
Average lifetime risk is 30% in cirrhotics without previous variceal bleed.
Predictors: Child class C, large varices, red wale markings, alcohol.
Volume resuscitate, pRBCs, and FFP transfusion.
Octreotide drip 50 mcg IV bolus then 50 mcg/hr.
Endoscopic band ligation slightly more effective than injection sclerotherapy
Rarely, urgent TIPS.
Prophylaxis with surveillance banding, non-selective beta blockers (nadolol or propranolol).
 Goal HR<25% of baseline ± nitrates
Non-variceal upper GI bleeding




Gastric varices accounts for 10% of all UGI bleeding in cirrhotics.
Portal hypertensive gastropathy accounts for up to 40% of all UGI bleeding in cirrhotics.
Average lifetime risk is 30% in cirrhotics without previous variceal bleed.
Treatment same as for esophageal variceal bleeding, although tend to be more difficult to treat.
 Propranolol is treatment of choice for portal hypertensive gastropathy.
Hepatic encephalopathy
 Manifestation of porto-systemic shunting with ammonia, and benzodiazepene-like false neurotransmitters
accounting for encephalopathy
 Often precipitated by infection (SBP), azotemia, GI bleeding, dietary indiscretion, sedatives, hypoxia,
hypotension, development of HCC
 Lactulose titrated to 2-4 bowel movements/day
Grading hepatic encephalopathy
(usually requires 30-60 g/day)
 Grade 1, restless, inverted sleep pattern, mild
 Neomycin (4-6 g/day) but caution because of
confusion, irritable with tremor and apraxia
potential nephrototoxicity

Grade 2, lethargy, slow responses,
 Metronidazole (800 mg/day) x 1 week as effective
inappropriate behaviors, disoriented to time,
as neomycin
Hepatorenal syndrome
asterixis, hypoactive DTRs
 Grade 3, omnolence but rousability, disoriented
to place and time, + asterixis, hyperactive
DTRs
 Grade 4, coma.
 Probability of occurrence 18% at 1 yr, 39% at 5 yr
 Poor prognostic event marked by azotemia and
oliguria refractory to volume challenges.
 Urine sediment is bland and low urine sodium
 Rule out other causes (hypovolemia, ATN, obstruction, drug effects, abdominal compartment syndrome
(check “bladder” pressure, abdominal compartment syndrome not likely <10 mm Hg and usually present
when >25 mm Hg)
 Precipitants: infection, over-diuresis, large volume paracentesis, aminoglycosides, NSAIDs
 Fluid challenges, remove all diuretics, nephrotoxins, and precipitants, consider large volume paracentesis
MGH Medical Housestaff Manual
60
20. End stage liver disease, complications




Midodrine (7.5-12.5 mg po tid) and octreotide (100-200 mcg sc tid) (Hepatology 1999;29:1690)
Norepinephrine and albumin (Hepatology 2002;36:374).
Transjugular intrahepatic portosystemic shunt (TIPS)
Transplant evaluation
Hepatopulmonary syndrome
 Rare complication of unknown etiology characterized by dyspnea, pulmonary vascular dilatation, and
hypoxemia (PaO2 <70 mm Hg); associated with orthodeoxia (upright hypoxia)
 Pathologically marked by diffuse (type I) large (type II) arterio-venous shunts in the pulmonary circulation
(possibly related to increased circulating NO)
 Diagnose by trans thoracic echo with bubble and macroaggregated radioactive albumin lung scan
 Improves with transplantation
 IR-guided embolization of AV communications if PaO2 <150 mm Hg on 100% O2
 Methylene blue (Ann Intern Med 2000;133:701)
Portopulmonary hypertension
 Rare cause of secondary pulmonary hypertension (all pts have signs of portal HTN)
 Present with DOE, syncope.
 Diagnosis of pulmonary hypertension by TTE and/or cath and demonstration of reversal of flow in portal vein
on Doppler ultrasound
 High mortality with liver transplant if mean PA pressures >35 mm Hg
 Responds to IV prostacyclin in some patients
Hepatic hydrothorax
 Right (66%) > bilateral (17%) = left (17%) pleural effusion which is transudative and often in association
with large ascites; caused by migration of fluid across diaphragm
Endocrinopathies
 Hypogonadism
 Thyroid dysfunction: high TSH, low T4, low T3, high rT3 akin to euthyroid sick syndrome
Vasculitis (hepatitis B, hepatitis C)
 Polyarteritis nodosa with hepatitis B
 Essential mixed cryoglobulinemia (type II cryoglobulinemia) and type III cryoglobulinemia with hepatitis C
Hepatocellular carcinoma
 Associated with cirrhosis (from any cause)
 Associated with hepatitis B carrier state
Deanna Nguyen, M.D.
MGH Medical Housestaff Manual
61
21. Bowel regimens
Bulking
 Psyllium (Metamucil)
Osmotic agents
Some literature regarding bowel regimens
 Psyllium superior to docusate sodium in patients
with chronic constipation in randomized double blind
study (Aliment Pharmacol Ther 1998;12:491-7)
 Comparison of Miralax with lactulose in chronic
constipation showed higher stool frequency with
Miralax (Gut 1999;44:226)
 “Although these [docusates, e.g. Colace] remain
very popular agents, clinical studies suggest that
docusates are of little use in the prophylaxis of
constipation in elderly bed-ridden patients” (Aliment
Pharmacol Ther 2001;15:749)
 Poorly absorbed salts
 Milk of magnesia
 Poorly absorbed disaccharides
 Lactulose. Metabolized in colon by bacteria
to short chain fatty acids.
 Sorbitol
 Polyethylene glycol
 GoLYTELY (polyethylene glycol 3350,
sodium sulfate)
 NuLYTELY (polyethylene glycol 3350, NaHCO3, KCl)
 Miralax (polyethylene glycol 3350)
Stimulant laxatives
 Docusates (Colace)
 Ionic detergents leading to stool softening; perfusion studies suggest that docusates inhibit fluid
absorption or stimulate secretion in jejunum.
 Diphenylmethane derivatives
 Phenolphthalein (withdrawn from U.S. market because of rodent data suggesting carcinogenesis).
 Bisacodyl (Dulcolax)
o Alters net fluid and electrolyte transport, direct effects on colonic motility (e.g. as suppository).
 Anthraquinones
 Senna (Senokot)
o Stimulates intestinal formation of prostaglandins, serotonin, and histamine to increase colonic secretions.
Other agents
 Enemas, disimpaction in selected circumstances (may need to individualize treatment)
 Neostigmine
 Acetylcholinesterase inhibitor, given 2 mg iv, useful for colonic decompression in Ogilvie’s syndrome (N
Engl J Med 1999;341:137).
 Side effects include symptomatic bradycardia requiring atropine, crampy abdominal pain, excessive
salivation and vomiting.
 Metoclopramide (Reglan)
 Dopamine antagonist, useful in diabetic gastroparesis; has rarely been associated with tardive dyskinesia
and extrapyramidal side effects.
 Erythromycin
 Given 200 mg iv q8h (not po); acts on motilin receptors.
 Improves gastric emptying in critically ill patients, delayed gastric emptying in diabetic gastropathy (Crit
Care Med 2000;28:2657); effects comparable to metoclopramide.
 Naloxone (Narcan) enterally
 In critically ill patients on fentanyl sedation, naloxone 8 mg po q6h decreased gastric tube reflux and
frequency of pneumonia, no effect on inducing bowel movements (Crit Care Med 2003;31:776).
 Various studies suggest reversal of opioid-associated constipation.
Evan Dellon, M.D.
Andrew Yee, M.D.
MGH Medical Housestaff Manual
62