LFTs/IBS
| Abnormal Liver Function Tests —G. Anton Decker, MD, Instructor of Medicine, Division of Gastroenterology,
Hepatology, and Internal Medicine, Mayo Clinic College of Medicine, Scottsdale, Arizona
|
| Introduction: elevations in liver function tests (LFTs) often not pathologic; few conditions (eg, acetaminophen [Tylenol]
toxicity) require immediate action; spontaneous resolution common
|
| Case: man, 30 yr of age, asymptomatic with total bilirubin 2.5 mg/dL, direct bilirubin 0.1 mg/dL, alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and alkaline phosphatase (ALP) within normal ranges; he drinks 1 glass of wine daily and
takes no medications; ultrasonography of liver reveals no abnormal findings; diagnosis—Gilbert’s syndrome; isolated unconjugated
hyperbilirubinemia clue to diagnosis; syndrome occurs in 5% of population; hemolysis ruled out in healthy patients
|
| Liver function tests: ALT, AST, ALP, bilirubin, γ-glutamyltransferase (GGT), albumin, and prothrombin time (PT); measures
of hepatocyte integrity and cholestasis; albumin and PT may reflect liver function, but not specific for liver disease;
extrahepatic sources of AST and ALP also exist
|
| Investigation: clinical context (eg, history, medications) important; pattern (cholestatic or hepatocellular) and degree of
abnormality (mild, moderate, or severe) give clues to diagnosis; abnormalities in AST and ALT generally reflect hepatocellular
injury; abnormalities in ALP and (to lesser extent) bilirubin generally reflect cholestatic injury; GGT sometimes
useful to determine source of ALP; general guidelines—immediately evaluate patients with LFTs >5 times upper limit
of normal (ULN) and signs and symptoms of liver disease; retest LFTs in 3 to 6 mo in patients with levels <3 times ULN,
in absence of concerning signs and symptoms; retest LFTs in 1 to 3 mo in patients with intermediate levels (3-5 times
ULN)
|
| Nonalcoholic fatty liver disease (NAFLD): most common cause of mild elevations in LFTs in western world (prevalence
≤23%); most patients asymptomatic, with elevated transaminases; NAFLD includes simple steatosis and nonalcoholic steatohepatitis
(NASH; inflammatory component); 60% of obese patients have simple steatosis, 20% to 25% haveNASH; over
5 yr, ≈15% of NASH cases progress to cirrhosis, and small percentage of these progress to hepatocellular carcinoma
(HCC); NASH may also progress directly to HCC; predictors of advanced liver disease—age >45 yr; body mass index
(BMI; weight (kg)/[height (m)]2 ) >30; AST to ALT ratio >1; presence of type 2 diabetes; liver biopsy recommended in
these patients to look for fibrosis and evidence of cirrhosis; management of NAFLD—weight loss important, although losing
weight too quickly may exacerbate NAFLD; tightening glucose control helpful (medications not proven effective); patients
with advanced liver disease require referral and close follow-up
|
| Medications and LFTs: many medications cause mild elevations in LFTs; persistent mild elevations unlikely to require
action; statins—1% to 3% of patients develop abnormalities in ALT >3 times ULN (indication for stopping statin); usually
occurs in first 3 mo of therapy; threshold arbitrarily established for clinical trials; no evidence that liver damage occurs
at this level; preexisting abnormalities in LFTs or chronic liver disease does not increase risk for hepatotoxicity on
statins (check LFTs 12 wk after starting statin; discontinue statin if LFTs >3-5 times ULN); general approach for medication-induced
elevations in LFTs—stop medication if LFTs >5 times ULN; retest in 3 mo if LFTs <3 times ULN; retest
in 1 mo if LFTs 3 to 5 times ULN
|
| Viral hepatitis: LFTs often fluctuate, especially in patients with hepatitis C; level of aminotransferase poor indicator of severity
of disease; screening—hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (HCV), and hepatitis A
virus (HAV) IgM
|
| Other sources of mild elevations in LFTs: hemochromatosis—look for transferrin saturation >45%; autoimmune
hepatitis—hypergammaglobulinemia common; clues to diagnosis include high total protein and low albumin; celiac
disease—up to 10% of patients with unexplained abnormalities in LFTs have celiac disease; á1 -antitrypsin deficiency—
screen for phenotype, because level of á1 -antitrypsin fluctuates; Wilson’s disease—younger patient presents with hemolysis
and psychiatric abnormalities; risk for fulminant liver disease
|
| Moderate to severe increases in LFTs: ischemic hepatitis—clinical setting (eg, recent surgery) important; AST peaks before
ALT, then bilirubin (bilirubin last to recover); most patients improve spontaneously with only supportive measures; viral
hepatitis—transaminases peak before jaundice appears; elevation generally less severe with HCV; symptoms more common
with HAV and hepatitis B virus (HBV); screening serologies important; acetaminophen toxicity—careful drug history required
(overdose not always intentional); 7.8 g causes hepatotoxicity in adults (less in alcoholic patients); ALT begins increasing
48 to 72 hr after ingestion; suspicion of acetaminophen toxicity warrants administration of N-acetylcysteine (Mucomyst);
acetaminophen levels unreliable within 4 hr of ingestion; acute biliary obstruction—acute obstruction of common bile duct
(eg, by gallstone) may cause massive elevations in AST and ALT, followed by ALP and bilirubin; alcoholic hepatitis—
moderate elevation in transaminases (200-400 U/L); AST to ALT ratio >1 or >2 important clue for diagnosis; may be acute
on chronic alcoholic hepatitis; biopsy may appear identical to NAFLD
|
| Cholestatic pattern: less common than hepatocellular pattern; usually associated with elevated ALP (but remember extrahepatic
origin of ALP) and bilirubin (less specific to cholestasis); drug-induced hepatotoxicity—normalization of LFTs
may require several months (8 mo in case of toxicity from amoxicillin-clavulanic acid [Augmentin]); medications causing
cholestasis include anabolic steroids, erythromycin, total parenteral nutrition (TPN), gold, imipramine, and estrogen; primary
biliary cirrhosis—uncommon condition, typically occurring in middle-aged women; presentation includes fatigue,
pruritus, and isolated elevated ALP; antimitochondrial antibodies present in 95% of patients; total IgM often elevated; hypercholesterolemia
caused by elevation in high-density lipoprotein (HDL); patients at risk for osteoporosis; treatment ursodeoxycholic
acid; primary sclerosing cholangitis—70% of cases associated with inflammatory bowel disease ([IBD];
sometimes asymptomatic); condition involves sclerosis of intrahepatic and extrahepatic bile ducts; magnetic resonance cholangiopancreatography
(MRCP) recommended for diagnosis; patients at high risk for cholangiocarcinoma and colon cancer
(independent of IBD); chronic biliary obstruction—intrahepatic or extrahepatic obstruction; bile ducts appear dilated on
ultrasonography; painless jaundice in older patient with dilated common bile duct suggests malignancy; sources of obstruction
include stones and liver masses (primary lesions or metastases)
|
| New Approaches to Irritable Bowel Syndrome —Richard A. Weisiger, MD, PhD, Professor, Department
of Medicine, and Director, Gastrointestinal Faculty Practice, University of California, San Francisco, School of Medicine
|
| Irritable bowel syndrome (IBS): group of functional bowel disorders; predominant features include abdominal pain or
discomfort associated with defecation or change in bowel habit and disordered defecation (constipation, diarrhea, or
combination); prevalence—≈19% of adults have IBS each year; disorder seen twice as often in women (but may reflect
difference in reporting)
|
| Issues in clinical care: patient expectations (ie, want doctor to prescribe something that makes them feel better or to make
treatable diagnosis) rarely met; most drugs not effective in controlled trials; no tests available to confirm diagnosis of
IBS; frustrated physicians may overdiagnose (eg, diverticulitis, endometriosis, adhesions), perform increasingly invasive
testing, overprescribe medications (including narcotics), or recommend unnecessary surgery; patient concerns—
diagnosis; control of symptoms; testing (uncomfortable and typically inconclusive); adequate time spent with physician
(who listens and appreciates underlying problems in life); solutions for stress; physician concerns—inability to help patient
and answer questions; fear of missing diagnosis; frustration with limited treatment options and use of medical resources
|
| Diagnosis: diagnosis of exclusion no longer encouraged (exhaustive testing costly and reinforces patient’s belief that organic
disease present); positive diagnosis based on clinical presentation and history has sensitivity and specificity >95%;
examination reveals nothing to account for symptoms and no alarm signs; additional work-up required in patients with
alarm signs (weight loss, anemia, elevated white blood cell [WBC] count, elevated sedimentation rate, bleeding, fever,
frequent nighttime symptoms, or onset of symptoms at >40 yr of age); limited diagnostic testing appropriate to age; social
history important for diagnosis and treatment; conditions associated with IBS—presence increases index of suspicion
for IBS; conditions include fibromyalgia, chronic fatigue syndrome, spastic bladder (interstitial cystitis), frequent headaches,
anxiety or panic disorder, depression, and allergies to multiple drugs
|
| Differential diagnosis: carbohydrate malabsorption—ingestion of lactose, sorbitol, or fructose may cause bloating,
pain, and diarrhea; history and avoidance trial usually sufficient to diagnose (hydrogen breath test confirms); celiac
sprue—patients with mild cases may not exhibit full syndrome; tissue transglutaminase or endomysial antibody test diagnostic
(biopsy of small bowel confirms, but usually not necessary); giardiasis—in patients with exposure to small
children or history of drinking from mountain streams; stool studies or response to empiric metronidazole (eg, Flagyl) diagnostic;
thyroid dysfunction—may cause constipation or diarrhea; IBD—inflammation (eg, elevated sedimentation
rate) key to diagnosis; others—chronic pancreatitis
|
| Work-up: careful, sympathetic history and thorough examination important; open-ended questioning (eg, “What’s your
life like right now?”) important for psychosocial assessment; respectful questioning can determine history of abuse (common
among patients with IBS); perform full work-up, looking for red flags and risk factors; discuss diagnosis, reassurance,
prognosis, and management plan
|
| Nonmedical options: stress reduction (eg, exercise, mediation, acupuncture, hypnosis) important; healthy diet; identification
of symptom triggers (eg, aerophagia, high intake of fats or carbohydrates, narcotic use); counseling cost-effective in
patients with history of abuse
|
| Medical options: standard antidiarrheal drugs and laxatives; fiber may improve bowel patterns, but patients sensitive to
gas and bulk; antispasmodic agents may help some patients, but value limited; sedatives have short-term benefit only
(speaker generally avoids); antidepressants—selective serotonin reuptake inhibitors (SSRIs) may help depression (but
not other symptoms); low doses (eg, 10 mg) of tricyclic antidepressants (TCAs) reduce pain in 70% of patients (require
6-8 wk to take effect); adverse effects include sedation and worsening of constipation; tegaserod (Zelnorm)—approved
for short-term treatment of constipation-predominant IBS in women (also for chronic idiopathic constipation); 6 mg bid
improves pain and appears safe (adverse effects include diarrhea); alosetron (Lotronex)—has restricted use for treatment
of diarrhea-predominant IBS; severe constipation and ischemic bowel may occur; appropriate labeling and informed
consent required; drug approved only for women, but speaker has used in men
|
| Pathophysiology: multiple etiologies likely; central nervous system (CNS)—persistent stress response leads to inappropriate
release of stress hormones and altered processing of pain signals; peripheral nervous system (PNS)—patients
with IBS have increased sensitivity at nerve endings and increased transmission of pain signals, resulting in visceral hypersensitivity;
gas formation—bacterial overgrowth may lead to increased formation of gas; mechanism must
explain—prevalence of anxiety and depression (study found 24% of patients with IBS have anxiety, 21% have depression,
21% have phobias, and 12% have panic disorder); altered sensation of pain (increased visceral pain and sensitivity
to gas in gut and associated emotional distress); overlap with other functional syndromes; correlation with recent life
stress (study found no improvement in symptoms in patients with continued severe stress); changes in intestinal motility;
increased mucosal secretion; prevalence in patients with history of abuse or neglect; triggering by episode of acute stress
|
| Inflammation: postinfectious IBS (PI-IBS)—follows 7% to 30% of cases of bacterial dysentery (eg, Campylobacter, Salmonella
, Shigella); accounts for 25% to 50% of all cases of IBS; indistinguishable from noninfectious form (including rate of
persistence); anxiety and depression not risk factors for acquiring PI-IBS, but condition more likely to persist in these patients;
other findings—low-grade inflammation in small bowel and colon (cell counts intermediate between healthy patients and patients
with IBD), but no endoscopic findings; possible causes—failure to down-regulate inflammatory response after infectious
enteritis; allergic reactions; altered bacterial flora; stress response; visceral hyperalgesia—caused by mucosal
inflammation; mast cells release histamines and other factors that affect muscle contractility and nerve function; stress can
cause degranulation of mast cells and may have role in dysmotility and pain of IBS
|
| Stress: sources include inflammation, pain, and perception of danger; brain hormones (eg, corticotropin-releasing factor
[CRF] and thyrotropin-releasing hormone [TRH]) initiate cascade that mediates autonomic, behavioral, and peripheral responses;
normally, homeostatic condition returns once danger passes; long-term stimulation of stress response may become
maladaptive
|
| Processing of pain: studies using functional magnetic resonance imaging (MRI) show patients with IBS have more activity
in regions of brain involved in emotional processing; anterior cingulate gyrus—region involved in integration of
danger and fear; left side (associated with logical processing) more active in healthy patients; right side (associated with
emotional processing) more active in patients with IBS during flare (left side more active when symptoms in remission)
|
| Animal model for IBS: newborn rats separated from mother for 3 hr daily (simulating neglect) appear to have baseline
visceral hypersensitivity, increased anxiety, and increased output of fecal pellets with stress as adults; medications—
drugs that target central pathways may offer effective treatment; Astressin, used in animal models, blocks CRH and
moderates stress response; hepatotoxicity prevents use in humans
|
Educational Objectives
| The goal of this activity is to improve efficiency and accuracy in diagnosing patients with abnormal liver function tests
(LFTs) and to provide information to aid in diagnosis and treatment of patients with irritable bowel syndrome (IBS). After
hearing and assimilating this program, the clinician will be better able to:
|
 | 1. Recognize patterns of elevations in LFTs and prioritize patients for evaluation.
|
| 2. Identify medications that may cause elevations in LFTs, determine when to discontinue medication, and discuss potential
for prolonged effects.
|
| 3. Clinically diagnose patients with IBS.
|
| 4. Establish management plans, including medical and nonmedical options for treatment of patients with IBS.
|
| 5. Discuss pathophysiology and the role of stress in the etiology of IBS.
|
Discussed on This Program
Acetaminophen (several trade names)
Acetylcysteine (n-acetylcysteine) [Acetadote, Mucomyst, Mucosil-10, -20]
Alosetron HCl [Lotronex]Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600,
Augmentin XR]
Erythromycin (several formulations and trade names)
Imipramine HCl [Tofranil]
Metronidazole [Flagyl, Flagyl 375, Flagyl ER, Flagyl IV, Flagyl IV RTU, Metric 21, MetroCream, MetroGel, MetroGel-
Vaginal, MetroLotion, Noritate, Protostat]
Sorbitol
Tegaserod maleate [Zelnorm]
Suggested Reading
Bjornsson E, Olsson R: Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 42:481, 2005;
Blanchard EB, et al: Prediction of treatment outcome among patients with irritable bowel syndrome treated with group
cognitive therapy. Behav Res Ther 44:317, 2006; Cammarota G, et al: High accuracy and cost-effectiveness of a biopsy-
avoiding endoscopic approach in diagnosing coeliac disease. Aliment Pharmacol Ther 23:61, 2006; Farrell GC, Larter
CZ: Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43:S99, 2006; Hadley SK, Gaarder SM:
Treatment of irritable bowel syndrome. Am Fam Physician 72:2501, 2005; Hussain Z, Quigley EM: Systematic review:
complementary and alternative medicine in the irritable bowel syndrome. Aliment Pharmacol Ther 23:465, 2006; Ioannou
GN, et al: The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-
2002. Am J Gastroenterol 101:76, 2006; Lawal A, et al: Novel evidence for hypersensitivity of visceral sensory neural
circuitry in irritable bowel syndrome patients. Gastroenterology 130:26, 2006; Malagelada JR: A symptom-based approach
to making a positive diagnosis of irritable bowel syndrome with constipation. Int J Clin Pract 60:57, 2006; Olden
KW: The use of antidepressants in functional gastrointestinal disorders: new uses for old drugs. CNS Spectr 10:891, 2005;
Riley TR 3rd , Kahn A: Risk factors and ultrasound can predict chronic hepatitis caused by nonalcoholic fatty liver disease.
Dig Dis Sci 51:41, 2006; Saito YA, et al: Diet and functional gastrointestinal disorders: a population-based case-control
study. Am J Gastroenterol 100:2743, 2005; Walgren JL, et al: Role of metabolism in drug-induced idiosyncratic
hepatotoxicity. Crit Rev Toxicol 35:325, 2005; Zar S, et al: Rectal afferent hypersensitivity and compliance in irritable
bowel syndrome: differences between diarrhoea-predominant and constipation-predominant subgroups. Eur J Gastroenterol
Hepatol 18:151, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Decker was recorded in Sedona, Arizona at Internal Medicine Update, sponsored by Mayo Clinic, College of Medicine,
Scottsdale and held October 6-9, 2005; Dr. Weisiger was recorded in San Francisco at Primary Care Medicine, sponsored
by University of California, San Francisco, School of Medicine, and held October 19-21, 2005. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
|
