INTERNAL MEDICINE BOARDS - PART 5 docx

D IFFERENTIAL Biliary obstruction stones, benign or malignant mass, autoimmune hepatitis, 1° and 2° sclerosing cholangitis, drug-induced cholestasis phenothiazines, steroids, TMP-SMX, to

Most common in the elderly and in patients with atherosclerotic or

cardiovas-cular disease Ranges from self-limited to life-threatening disease Watershed areas (the splenic flexure and rectosigmoid junction of the colon) are the

most common sites affected Exsanguination and infarction are uncommon

S YMPTOMS /E XAM

■ Crampy left lower abdominal pain, hematochezia, nausea

■ Abdominal exam is benign or reveals mild LLQ tenderness

D IFFERENTIAL

IBD, infectious colitis, diverticulitis

D IAGNOSIS

■ Labs: Leukocytosis, anemia.

■ AXR: “Thumbprinting” is seen on the colon wall.

■ CT: Shows bowel wall thickening, luminal dilation, and pericolonic fat

stranding Vascular occlusion (e.g., mesenteric venous thrombosis) is common

un-■ Flexible sigmoidoscopy: Contraindicated if peritoneal signs are present Performed with minimal insufflation Look for segmental changes sparing the rectum (due to preserved collateral circulation from hemorrhoidal

plexus) and hemorrhagic nodules Pale, dusky, ulcerative mucosa

T REATMENT

■ Correct hypotension, hypovolemia, and cardiac arrhythmias

■ Minimize vasopressors; give broad-spectrum IV antibiotics

■ Monitor for progression with serial exams and radiographs

■ If there are signs of infarction (guarding, rebound tenderness, fever), arotomy, revascularization, or bowel resection may be needed

lap-PA N C R E AT I C D I S O R D E R S Acute Pancreatitis

In the United States, > 80% of acute pancreatitis cases result from bingedrinking or biliary stones; only 5% of heavy drinkers develop pancreatitis.Twenty percent of cases are complicated by necrotizing pancreatitis Etiolo-gies are as follows:

■ EtOH and gallstones and, to a lesser extent, trauma.

■ Drugs: Azathioprine, pentamidine, sulfonamides, thiazide diuretics, 6-MP,

valproic acid, didanosine

■ Metabolic: Hyperlipidemia or hypercalcemia.

■ Mechanical: Pancreas divisum, sphincter of Oddi dysfunction, mass.

■ Infectious: Viruses (e.g., mumps) and, to a lesser extent, bacteria and

para-sites (e.g., Ascaris lumbricoides).

■ Other: Scorpion bites, hereditary pancreatitis (an autosomal-dominant

mutation of the trypsinogen gene), CF, pregnancy

Ischemic colitis typically

affects the colonic

“watershed” areas of the

splenic flexure and rectosigmoid junction but

spares the rectum.

Ascaris lumbricoides causes

up to 20% of cases of acute

pancreatitis in Asia.

Gallstones and alcohol are the

main causes of pancreatitis in

the United States.

■ Presents with sudden-onset, persistent, deep epigastric pain, often with

ra-diation to the back, that worsens when patients are supine and improves

when they sit or lean forward.

■ Severe nausea, vomiting, and fever are also seen

E XAM

■ Exam reveals upper abdominal tenderness with guarding and rebound

■ Other findings include the following:

■ Severe cases: Distention, ileus, hypotension, tachycardia.

■ Rare: Umbilical (Cullen’s sign) or flank (Grey Turner’s sign)

ecchy-mosis

■ Other: Mild jaundice with stones or xanthomata with hyperlipidemia.

D IFFERENTIAL

Biliary colic, cholecystitis, mesenteric ischemia, intestinal obstruction/ileus,

perforated hollow viscus, inferior MI, dissecting aortic aneurysm, ectopic

pregnancy

D IAGNOSIS

■ Labs (see also Table 7.13):

■ Leukocytosis (10,000–30,000/μL); elevated amylase (more sensitive)

and lipase (more specific)

■ There is no clinical use for serial amylase or lipase

■ High serum glucose

■ An ALT > 3 times normal suggests biliary stones over EtOH; an

AST:ALT ratio > 2 favors EtOH CRP declines with improvement.

■ Differential for elevated amylase: Pancreatitis, pancreatic tumors,

chole-cystitis, perforation (esophagus, bowel), intestinal ischemia or infarction,

appendicitis, ruptured ectopic pregnancy, mumps, ovarian cysts, lung

can-cer, macroamylasemia, renal insufficiency, HIV, DKA, head trauma

Li-pase is usually normal in nonpancreatic amylase elevations.

■ AXR: May show gallstones, “sentinel loop” (an air-filled small bowel in

the LUQ), and “colon cutoff sign” (abrupt ending of the transverse

colon)

■ RUQ ultrasound: Reveals cholelithiasis without cholecystitis

Choledo-cholithiasis (common duct stones) are often missed or have passed

■ CT: Performed initially to exclude abdominal catastrophes At 48–72

hours, exclude necrotizing pancreatitis There is an ↑ risk of renal failurefrom contrast dye

pancre-■ For gallstone pancreatitis (elevated serum bilirubin, signs of biliary

sep-sis), perform ERCP for stone removal and cholecystectomy following

re-covery but prior to discharge.

or-■ Pancreatic pseudocyst: A collection of pancreatic fluid walled off by

gran-ulation tissue Occurs in approximately 30% of cases but resolves neously in about 50% Drainage is not required unless the pseudocyst ispresent> 6–8 weeks and is enlarging and symptomatic

sponta-■ Other: Pseudoaneurysm, renal failure, ARDS, splenic vein thrombosis

(which can lead to isolated gastric varices)

smok-■ EtOH (80%) and, to a lesser extent, hereditary pancreatitis (CF,

trypsino-gen mutation)

■ Autoimmune: Rare and associated with diffuse enlargement of the

pan-creas,↑ IgG4, and autoantibodies; associated with other autoimmune orders (e.g., Sjögren’s, SLE, 1° sclerosing cholangitis)

dis-■ Obstructive: Pancreas divisum, sphincter of Oddi dysfunction, mass.

■ Metabolic: Malnutrition, hyperlipidemia, hyperparathyroid-associated

hy-percalcemia

For persistent pancreatitis, no

improvement on antibiotics (>

1 week), or suspicion of

infected necrosis, consider CT

with FNA to rule out infected

necrosis, which requires

surgical debridement.

■ Presents with recurrent, deep epigastric pain, often radiating to the back,

that worsens with food intake and when patients lie supine and improves

when they sit or lean forward Episodes may last anywhere from hours to

2–3 weeks

■ Also presents with anorexia, fear of eating (sitophobia), nausea/vomiting,

and, later, weight loss and steatorrhea

E XAM

■ Exam is normal Mild to moderate upper abdominal tenderness may be

found during episodes

■ Rarely, there may be a palpable epigastric mass (pseudocyst) or spleen

(from splenic vein thrombosis)

D IFFERENTIAL

Biliary colic, mesenteric ischemia, PUD, nonulcer dyspepsia, inferior MI,

perforation, IBS, drug-seeking behavior

D IAGNOSIS

Diagnosis is as follows (see also Table 7.14):

■ No single test is adequate; routine labs are normal Amylase and lipase are

not always elevated during episodes

■ Functional tests:

■ Often normal in “small duct” chronic pancreatitis; not until 30–50%

of the gland is destroyed

■ Seventy-two-hour fecal fat test on 100-g/day fat diet:  in the

pres-ence of > 7 g of fat in stool

■ Stool chymotrypsin and elastase: Absent or low levels.

■ Secretin test: Most sensitive, but impractical Give IV secretin and

then measure pancreatic secretion via a nasobiliary tube

■ Structural tests: Except for endoscopic ultrasound (EUS), imaging studies

are insensitive, as architectural changes do not occur until late in the

dis-ease course; diagnosis is improved with EUS +/− FNA Pancreatic

calcifi-cations are visualized on plain AXRs (30%); “big duct” injury is seen on

CT

Seen on ultrasound or CT Yes No

Etiology EtOH Non-EtOH >> EtOH

Loss of function (exocrine/endocrine) Common Less common

Responsive to decompression Often Rarely

(stenting, surgery)

Chronic pancreatitis of the

“small duct” type may exhibit very subtle structural changes and is often associated with normal functional tests but marked symptoms.

■ Histology: The gold standard, but impractical; obtained by EUS FNA.

Reveals fibrosis, mixed lymphocyte and monocyte infiltrate, and tural changes

architec-T REATMENT

■ Alcohol abstinence

■ Fat-soluble vitamins (vitamins A, D, E, and K); pancreatic enzymes

■ Pain control with narcotics (avoid morphine) and celiac plexus injection

■ ERCP with short-term pancreatic duct stenting and stone removal

■ Surgical therapy is appropriate for intractable pain and failure of medical

therapy; modalities include pancreatectomy, pancreaticojejunostomy(Puestow), and pseudocyst drainage

C OMPLICATIONS

■ Malabsorption: Fat-soluble vitamins (A, D, E, and K); pancreatic

en-zymes

■ Metabolic bone disease: Osteopenia (33%) and osteoporosis (10%)

Man-age with calcium, vitamin D, and bisphosphonates

■ Other: Brittle DM, pancreatic pseudocyst, pseudoaneurysm, hemosuccus

pancreaticus (bleeding from the pancreatic duct into the GI tract), splenicvein thrombosis, pancreatic cancer

B I L I A RY D I S E A S E

Tables 7.15 and 7.16 classify diseases with jaundice and biliary tract disease

Cholelithiasis (Gallstones) and Acute Cholecystitis

More common in women; incidence ↑ with age In the United States, 10% ofmen and 20% of women > 65 years of age are affected; > 70% are cholesterolstones (see Table 7.17) Among patients with incidental asymptomatic gall-stones, only 15% have biliary colic at 10 years, and 2–3% have cholecystitis/cholangitis

■ Cholecystitis: The most common complication of cholelithiasis More

than 90% of cases are due to cholelithiasis with stone impacted in the tic duct Spontaneous resolution occurs in > 50% of cases within 7–10days

cys-■ Acalculous cholecystitis (without gallstones): Usually seen in critically ill

patients with no oral intake or following major surgical procedures; occursafter ischemia-related chronic gallbladder distention

S YMPTOMS

■ Cholelithiasis: Often asymptomatic or may present as follows:

■ Common: Biliary colic (crampy, wavelike RUQ pain), abdominal

bloating, dyspepsia

■ Uncommon: Nausea/vomiting (except in small bowel obstruction from gallstone ileus).

■ Cholecystitis: Sudden-onset, severe RUQ or epigastric pain that may

radi-ate to the right shoulder, accompanied by nausea/vomiting and fever.Jaundice suggests common bile duct stones (choledocholithiasis) or com-pression of the common bile duct by an inflamed, impacted cystic duct

(Mirizzi’s syndrome).

Acalculous cholecystitis is

generally seen in the critically

ill with no oral intake or after

major surgical procedures.

■ Cholecystitis: RUQ tenderness and voluntary guarding; Murphy’s sign

(inspiratory arrest with palpation of the RUQ); fever; jaundice in < 25% of

■ Labs: Leukocytosis with neutrophil predominance; elevated total

bilirubin (1–4 mg/dL) and transaminases (2–4 times normal) even

without choledocholithiasis Elevated alkaline phosphatase and

amy-lase

■ RUQ ultrasound: Less sensitive than HIDA scan but more readily

available Shows gallbladder wall thickening, pericholecystic fluid,

and localization of stones A radiographic Murphy’s sign (focal

↑ bilirubin production (e.g., hemolytic anemias, hemolytic reactions, hematoma, pulmonary infarction).

Impaired bilirubin uptake and storage (e.g., posthepatitis hyperbilirubinemia, Gilbert’s syndrome, Crigler-Najjar syndrome, drug reactions).

Hereditary cholestatic syndromes: Faulty excretion of bilirubin

conjugates (e.g., Dubin-Johnson syndrome, Rotor’s syndrome).

Hepatocellular dysfunction:

■ Biliary epithelial damage (e.g., hepatitis, hepatic cirrhosis).

■ Intrahepatic cholestasis (e.g., certain drugs, biliary cirrhosis, sepsis, postoperative jaundice).

■ Hepatocellular damage or intrahepatic cholestasis resulting from miscellaneous causes (e.g., spirochetal infections, infectious mononucleosis, cholangitis, sarcoidosis, lymphomas, industrial toxins).

Biliary obstruction: Choledocholithiasis, biliary atresia,

carcinoma of the biliary duct, sclerosing cholangitis, choledochal cyst, external pressure on the common duct, pancreatitis, pancreatic neoplasms.

Unconjugated hyperbilirubinemia (predominant

■ HIDA scan: High sensitivity (95%) and specificity (90%) Assesses

cystic duct patency;  in the setting of a  gallbladder uptake with

preserved excretion into the small bowel CCK stimulation assesses

gallbladder contractility and aids in the diagnosis of acalculous cystitis

Asymptomatic None Normal Ultrasound None.

Porcelain gallbladder Usually asymptomatic; Normal X-ray or CT Laparoscopic

high risk of gallbladder cholecystecomy cancer.

Acute cholecystitis Epigastric or RUQ Leukocytosis Ultrasound, HIDA Antibiotics,

Murphy’s sign.

Chronic cholecystitis Biliary colic, constant Normal Oral cholecystography, Laparoscopic

epigastric or RUQ ultrasound (stones), cholecystectomy pain, nausea cholecystectomy

(nonfunctioning gallbladder).

Choledocholithiasis Asymptomatic or Cholestatic LFTs; Ultrasound (dilated Endoscopic

biliary colic, jaundice, leukocytosis and ducts), ERCP sphincterotomy and fever; gallstone blood cultures in stone extraction; pancreatitis cholangitis; elevated antibiotics for

amylase and lipase cholangitis.

in pancreatitis.

Adapted, with permission, from Tierney LM et al Current Medical Diagnosis & Treatment, 44th ed New York: McGraw-Hill, 2005:

663.

■ Consider prophylactic cholecystectomy.

■ Cholecystectomy can be postponed until recurrent symptoms are seen

■ The risk of recurrent symptoms is 30–50% per year; the risk of

com-plications is 1–2% per year.

■ Cholecystitis:

■ Antibiotics can be withheld in the setting of mild and

uncompli-cated disease.

■ IV antibiotics: Provide coverage of gram-enteric bacteria and

ente-rococcus with antibiotics such as ampicillin and gentamicin (or

ampi-cillin/sulbactam if the patient is ill)

■ Bowel rest

■ Cholecystectomy should be performed after symptom resolution but

prior to discharge

C OMPLICATIONS

■ Gangrenous cholecystitis: The most common complication of

cholecysti-tis (affects up to 20%), particularly in diabetics and the elderly Patients

ap-pear septic

■ Emphysematous cholecystitis: 2° infection of the gallbladder with

gas-forming organisms More common in diabetics and the elderly; associated

with high mortality Gangrene and perforation may follow

■ Cholecystenteric fistula: Uncommon Stone erodes through the

gallblad-der into the duodenum Large stones (> 2.5 cm) can cause small bowel

obstruction (gallstone ileus).

■ Mirizzi’s syndrome: Common bile duct obstruction by an inflamed

im-pacted cystic duct Uncommon

■ Gallbladder hydrops.

■ Porcelain gallbladder: Intramural calcification Associated with an ↑ risk

of gallbladder cancer; cholecystectomy is indicated

Regional/ethnic Western countries, Pima Africa, Asia Africa, Asia.

predictors Indians, Caucasians >>

blacks.

Risk factors Age, female gender, Chronic hemolysis (sickle cell), Biliary infections, foreign

pregnancy, estrogens, DM, cirrhosis, high-protein diet bodies (stents, sutures), obesity, rapid weight loss, low-protein diet.

elevated triglycerides, prolonged fasting, ileal

disease (Crohn’s), ileal

resection, CF.

Choledocholithiasis and Cholangitis

Choledocholithiasis is defined as stones in the common bile duct tis can be defined as biliary tree obstruction and subsequent suppurative in-fection

■ Cholangitis: Similar to cholecystitis but frequently more severe,

present-ing with fever, jaundice, and RUQ pain (Charcot’s triad) May also clude mental status changes and hypotension (Reynolds’ pentad)

in-E XAM

■ Choledocholithiasis: Exam is normal or reveals mild RUQ tenderness

along with jaundice

■ Cholangitis:

(> 80%), hypotension, and altered mental status (15%)

■ Charcot’s triad (RUQ pain, jaundice, fever): Present in only 70% of

patients

■ Reynolds’ pentad (Charcot’s triad plus hypotension and altered mental status): Points to impending septic shock.

D IFFERENTIAL

■ Choledocholithiasis: Mass lesions (e.g., pancreatic and ampullary

carci-noma, cholangiocarcicarci-noma, bulky lymphadenopathy), parasitic infection(e.g., ascariasis), AIDS cholangiopathy, 1° sclerosing cholangitis, recurrentpyogenic cholangitis

■ Cholangitis: Perforated peptic ulcer, hepatitis, acute pancreatitis,

appen-dicitis, hepatic abscess, diverticulitis, right-sided pneumonia

D IAGNOSIS

■ Choledocholithiasis:

■ Labs: No leukocytosis; elevated total bilirubin (> 2 mg/dL),

transami-nases (2–4 times normal), and alkaline phosphatase

■ RUQ ultrasound: Has low sensitivity (< 50%).

■ CT: Has higher sensitivity than RUQ ultrasound.

■ Cholangitis:

■ Labs: Leukocytosis with neutrophil predominance; elevated total

bilirubin (> 2 mg/dL), transaminases (> 2–4 times normal), alkalinephosphatase, and amylase; bacteremia

■ RUQ ultrasound: Shows dilation of the common bile duct and

cholelithiasis Less likely to visualize choledocholithiasis

■ ERCP: Perform < 48 hours after presentation, ideally after IV otics and fluids Requires sedation Both diagnostic and therapeutic

antibi-■ MRCP: Noninvasive and sensitive for diagnosis.

■ EUS: The most sensitive diagnostic study, but not readily available.

■ Percutaneous transhepatic cholangiography (PTHC): An alternative

if ERCP is unavailable, unsafe, or unsuccessful Does not require tion

seda-Charcot’s triad = RUQ pain,

jaundice, and fever/chills.

Reynolds’ pentad = Charcot’s

triad plus hypotension and

altered mental status.

■ High suspicion (total bilirubin > 2, alkaline phosphatase > 150,

ele-vated AST/ALT): ERCP with sphincterotomy/stone removal prior to

surgery followed by laparoscopic cholecystectomy

■ Intermediate suspicion: Intraoperative cholangiography, MRCP, or

EUS If MRCP or EUS is for choledocholithiasis, proceed to ERCP

■ Cholangitis:

■ Broad-spectrum IV antibiotics: IV ampicillin/sulbactam (Unasyn) or

ticarcillin/clavulanate (Timentin) If the patient is responsive to

antibi-otics, biliary decompression can be elective; otherwise, it is indicated

emergently

■ ERCP: Biliary decompression and drainage (sphincterotomy, stone

re-moval, biliary stenting)

■ PTHC: A temporary alternative to ERCP that allows for biliary

decom-pression (stenting and drainage)

■ Cholecystectomy after recovery for cholangitis due to gallstones

■ Recurrent pyogenic cholangitis: Affects Southeast Asians between 20

and 40 years of age; characterized by pigmented intrahepatic bile duct

stones, biliary strictures, and repeated cholangitis Treatment includes

stenting and drainage Often isolated to the left lobe of the liver;

resec-tion may be considered

■ Labs: Markedly elevated alkaline phosphatase.

■ ERCP: Intra- and/or extrahepatic biliary stricturing; papillary stenosis.

■ Aspiration and culture of bile are key to diagnosis.

T REATMENT

■ ERCP with sphincterotomy and biliary stenting

■ IV antibiotics based on bile cultures

■ Treat underlying immunosuppression/HIV

1 ° Sclerosing Cholangitis

A chronic cholestatic disease characterized by fibrosing inflammation of the

Most common among middle-aged males; median survival from the time of

diagnosis is 12 years Commonly associated with IBD (more frequently

ulcer-ative colitis than Crohn’s) and, to a lesser extent, with other autoimmune orders (celiac sprue, sarcoidosis, Sjögren’s syndrome, SLE, autoimmune hep-atitis) Also associated with an ↑ risk of cholangiocarcinoma

2° sclerosing cholangitis—biliary stones, congenital anomalies, infections,

AIDS cholangiopathy, recurrent pyogenic cholangitis

D IAGNOSIS

■ Maintain a high clinical suspicion in patients with IBD, as the diagnosis

of IBD typically precedes that of 1° sclerosing cholangitis Diagnosis

can be confirmed only by ERCP Magnetic resonance cholangiography(MRC) is less sensitive and less specific

■ Labs: Look for a cholestatic pattern consisting of alkaline phosphatase > 1.5

times normal for six months plus a modest ↑ in bilirubin and transaminases

■ Autoantibodies: The sensitivity of p-ANCA is 70%; that of ANA is 25%.

■ Liver biopsy: Look for pericholangitis and the classic “onion skin”

periductal fibrosis, focal proliferation and obliteration of bile ducts,cholestasis, and copper deposition

■ ERCP: Shows irregularity of the intra- and extrahepatic biliary tree, cally with a “beads on a string” appearance 2° causes of sclerosing cholangitis usually have only extrahepatic bile duct involvement except

classi-with recurrent pyogenic cholangitis (intrahepatic biliary dilation andstones)

T REATMENT

complications Medical therapy to prevent or delay disease progression islargely ineffective

■ Symptom control: Treat pruritus (cholestyramine, ursodiol,

phenobarbi-tal, rifampin)

■ Medical therapy: Immunosuppression (corticosteroids, cyclosporine,

aza-thioprine, methotrexate), antifibrogenics (colchicine), others

(penicil-lamine, ursodeoxycholic acid) The natural history of 1° sclerosing cholangitis is not significantly changed by current medical therapy.

■ Liver transplantation: The treatment of choice for end-stage liver failure;

five-year survival is 75%

C OMPLICATIONS

■ Steatorrhea/fat-soluble vitamin deficiency: Treat with bile acids, digestive

enzymes, and vitamins A, D, E, and K

■ Metabolic bone disease: Treat with Ca++and bisphosphonates

■ Recurrent bacterial cholangitis and dominant strictures: Treat with

an-tibiotics and biliary stent and drainage

■ Other: Biliary stones, cholangiocarcinoma, portal hypertension, end-stage

liver disease

Seventy-five percent of

patients with 1 ° sclerosing

cholangitis have IBD, but the

reverse is the case for only a

small subset of IBD patients.

1 ° sclerosing cholangitis is

diagnosed by ERCP and shows

a “beads on a string”

appearance involving both

intra- and extrahepatic bile

ducts.

A chronic cholestatic disease that primarily affects middle-aged women of all

races Prevalence is 19–240 cases in one million; 90–95% are women Age at

onset is 30–70; often associated with autoimmune disorders such as Sjögren’s,

RA, thyroid disease, celiac sprue, and CREST syndrome

S YMPTOMS

May be asymptomatic (50–60% at the time of diagnosis) or present with

fa-tigue, severe and intractable pruritus prior to jaundice, and malabsorptive

diarrhea Commonly associated with Sjögren’s syndrome, arthritis, and

Ray-naud’s phenomenon

E XAM

■ Exam reveals hepatomegaly, splenomegaly, skin pigmentation,

excoria-tions (from pruritus), xanthelasma, and xanthomas Kayser-Fleischer rings

are rare (result from copper retention, as in Wilson’s disease)

■ Late findings include jaundice and the stigmata of cirrhosis

D IFFERENTIAL

Biliary obstruction (stones, benign or malignant mass), autoimmune hepatitis,

1° and 2° sclerosing cholangitis, drug-induced cholestasis (phenothiazines,

steroids, TMP-SMX, tolbutamide), infiltrative diseases (sarcoidosis,

■ Cholestatic pattern: Look for an alkaline phosphatase level > 3–4

times normal, an elevated GGT, and a slight ↑ in transaminases

Serum bilirubin is normal early in disease but is elevated later in the

disease course

■ Serum autoantibodies: Antimitochondrial antibodies (AMA) are

de-tected in 95% of cases ANA (70%), SMA (66%), RF (70%), and

an-tithyroid antibodies (40%) are also seen

■ Other: ↑ serum IgM, total cholesterol, HDL, ceruloplasmin, and

uri-nary copper

■ Imaging: Ultrasound is initially useful for excluding biliary tract

obstruc-tion; MRI/CT can show nonprogressive periportal adenopathy Signs of

portal hypertension are usually absent at the time of diagnosis

■ Liver biopsy: Important for diagnosis, staging, and prognosis The

pathog-nomonic finding is the “florid” duct lesion (duct degeneration with

periductular granulomatous inflammation), which is uncommon

■ ERCP: Needed only to exclude 1° and 2° sclerosing cholangitis.

T REATMENT

■ Disease-modifying therapy has limited efficacy Symptom control and the

prevention and treatment of complications are most important in

manage-ment

■ Ursodeoxycholic acid: The only FDA-approved disease-modifying agent;

promotes endogenous bile acid secretion and may also have immunologic

Antimitochondrial antibody (present in 95% of patients) and elevated serum IgM are the best laboratory diagnostic tools for 1 ° biliary cirrhosis.

com-■ Liver transplantation: The most effective treatment for decompensated 1°

biliary cirrhosis Five-year survival is 85%; rates of recurrent 1° biliary rhosis at 3 and 10 years are 15% and 30%, respectively The need for livertransplantation can be predicted by the Mayo Clinic model (based on pa-tient age, total bilirubin, PT, and serum albumin)

cir-C OMPLICATIONS

■ Malabsorption: Treat with fat-soluble vitamins (A, D, E, and K) and

pan-creatic enzymes

■ Metabolic bone disease: Osteopenia (affects 33%) and osteoporosis

(af-fects 10%) Manage with calcium, vitamin D, and bisphosphonates

■ Cirrhosis: Late ascites, encephalopathy, portal hypertension.

H E PAT I T I S Hepatitis A (HAV) and Hepatitis E (HEV) Spread by fecal-oral transmission; cause acute (not chronic) hepatitis More

common in developing countries The annual incidence of HAV in the

United States is 70,000, whereas HEV is rare and limited to travelers of demic regions (Southeast and Central Asia, the Middle East, Northern

en-Africa, and, to a lesser extent, Mexico) HAV is typically asymptomatic, nign, and self-limited in children but can range from mild to severe acutehepatitis in adults The rate of fatal acute liver failure from HAV is < 4% inpatients< 49 years of age but can be as high as 17% in those > 49 years of age

be-HEV is more severe than HAV, particularly in pregnancy, a setting in which mortality is approximately 20%.

■ Figure 7.4 illustrates the typical course of HAV

■ HAV: Anti-HAV IgM (acute infection); anti-HAV IgG (prior exposure,

vaccination); anti-HAV total measures IgM and IgG (acute infection,prior exposure, vaccination)

■ HEV: Anti-HEV IgM (acute infection); anti-HEV (prior exposure).

HAV and HEV cause variably

severe acute hepatitis but do

not cause chronic hepatitis.

■ Vaccination: The HAV vaccine is safe and effective, but no vaccine for

HEV is currently available

■ Indications for HAV vaccine: Travelers to endemic regions, men who

have sex with men, IV drug users, Native Americans, those with chronic

liver disease (all HCV ), food handlers, day care center workers

■ HAV immunoglobulin: Effective for postexposure prophylaxis For those

traveling immediately to endemic areas, supplement with the first HAV

vaccine shot

Hepatitis B (HBV) and Hepatitis D (HDV)

Some 400 million people worldwide have chronic HBV, including > 1

mil-lion in the United States Transmission can be perinatal (the most common

cause worldwide), sexual, or percutaneous Age at infection is inversely

re-lated to the risk of chronic infection Of all patients with chronic HBV,

15–20% develop cirrhosis and 10–15% develop hepatocellular carcinoma

HDV infection requires HBV coinfection In the United States, HDV is

found primarily among IV drug users and hemophiliacs

S YMPTOMS

■ Acute HBV: Presents with flulike illness, malaise, weakness, low-grade

fever, serum sickness–like symptoms (arthritis, urticaria, angioedema), and

RUQ pain followed by jaundice (see Figure 7.5)

■ Chronic HBV: Can be asymptomatic.

■ Extrahepatic manifestations: Serum sickness, polyarteritis nodosa,

glomerulonephritis

(Reproduced, with permission, from Kasper DL et al Harrison’s Principles of Internal Medicine,

16th ed New York: McGraw-Hill, 2005: 1822.)

HCV.

■ Acute: Icteric sclera, arthritis, RUQ tenderness.

■ Chronic: Stigmata of cirrhosis (spider angiomata, palmar erythema,

gyne-comastia)

D IFFERENTIAL

■ Other acute viral diseases: HAV, HCV, mononucleosis, CMV, HSV.

■ Spirochetal (leptospirosis, syphilis) and rickettsial disease (Q fever).

■ Other chronic liver diseases: Autoimmune disease, hemochromatosis, α1antitrypsin deficiency, Wilson’s disease, alcoholic/nonalcoholic steatohep-atitis

-D IAGNOSIS

■ HBsAg: Surface antigen indicates active infection (see Table 7.18).

■ Anti-HBs: Antibody to HBsAg indicates past viral infection or

immuniza-tion

■ Anti-HBc: IgM is an early marker of infection; IgG is the best marker for

prior HBV exposure IgM may also become detectable in reactivation ofHBV

■ HBeAg: Proportional to the quantity of intact virus and therefore ity Some HBV variants (called precore mutants) cannot make HBeAg.

infectiv-Precore mutants have lower spontaneous remission, are less responsive totreatment, and are associated with a higher risk of cirrhosis and hepatocel-lular carcinoma Precore mutants are diagnosed by their high HBV DNA

con-■ Liver biopsy: Not routinely needed prior to treatment Indicated if the

di-agnosis is in question or to determine the degree of inflammation or sis/cirrhosis

(Reproduced, with permission, from Kasper DL et al Harrison’s Principles of Internal Medicine,

16th ed New York: McGraw-Hill, 2005: 1825.)

Anti-HBc IgM anti-HBc

■ Acute exposure/needlestick prophylaxis: The CDC recommends that

hepatitis B immune globulin (HBIG) be given within 24 hours along

with vaccine if the patient was not previously immunized.

■ Pegylated interferon-α 2a : Given SQ; associated with many side effects

(e.g., constitutional, psychiatric, bone marrow toxicity, flare of

autoim-mune disease, hepatic decompensation) Contraindicated in cirrhosis The

best responses to treatment are obtained with active hepatic inflammation

(high ALT) and low HBV DNA levels

■ Lamivudine: Given PO Well tolerated, but resistance may develop.

■ Adefovir: Given PO Well tolerated and may be used to treat

lamivudine-resistant virus; has lower rates of resistance than lamivudine Associated

with renal insufficiency

■ Newer antivirals: Entecavir, telbivudine, emtricitabine/tenofovir (used for

HIV coinfection)

■ Treat HDV by treating HBV

■ HBV cirrhosis: Indefinite treatment with an antiviral agent.

■ Liver transplantation: The treatment of choice for decompensated

cirrho-sis

Hepatitis C (HCV)

Transmitted by percutaneous or mucosal blood exposure Risk factors include

blood transfusions before 1992, IV drug use, and occupational exposure

(needlesticks) Spontaneous resolution occurs in 15–45% of patients, with the

+ − IgM + − Acute hepatitis B.

+ − IgG a + − Chronic hepatitis B with active

viral replication.

+ − IgG − + Chronic hepatitis B with low

viral replication.

+ + IgG + or − + or − Chronic hepatitis B with

heterotypic anti-HBs (about 10% of cases).

− − IgM + or − − Acute hepatitis B.

− + − − − Vaccination (immunity).

− − IgG − − False ; less commonly,

infection in remote past.

a Low levels of IgM anti-HBc may also be detected.

Reproduced, with permission, from Tierney LM et al Current Medical Diagnosis & Treatment,

44th ed New York: McGraw-Hill, 2005: 634.

Needlestick transmission rates follow the rule of 3’s: HBV 30%, HCV 3%, HIV 0.3%.

S YMPTOMS

■ Acute HCV: Presents with flulike illness, malaise, weakness, low-grade

fever, myalgias, and RUQ pain followed by jaundice Only 30% of patientsare symptomatic in acute disease

■ Chronic HCV: Often asymptomatic, or may present with mia associated with a vasculitic skin rash (leukocytoclastic vasculitis), arthralgias, sicca syndrome, and glomerulonephritis In the setting of cir-

cryoglobuline-rhosis, presents with fatigue, muscle wasting, dependent edema, and easybruising

E XAM

■ Acute: Icterus; RUQ tenderness.

■ Chronic: Stigmata of cirrhosis (spider angiomata, palmar erythema,

gyne-comastia, ascites)

D IFFERENTIAL

■ Other acute viral diseases: HAV, HBV, mononucleosis, CMV, HSV.

■ Spirochetal (leptospirosis, syphilis) and rickettsial disease (Q fever).

■ Other chronic liver diseases: HBV, hemochromatosis, α1-antitrypsin ciency, Wilson’s disease, nonalcoholic steatohepatitis, autoimmune hepati-tis

defi-D IAGNOSIS

■ Screening: HCV antibody (4–6 weeks after infection), qualitative PCR(in acute infection; can be  1–2 weeks after infection) Screen patientswith risk factors or persistently elevated transaminases

■ Confirmatory: Qualitative PCR or recombinant immunoblot assay (RIBA).

■ Prognostic: Liver biopsy.

T REATMENT

■ Regimen: Treat with SQ interferon (pegylated or standard) and PO

rib-avirin × 24 weeks (non–genotype 1) or × 48 weeks (genotype 1) Checkquantitative RNA at 12 weeks; if there is less than a 2-log drop, considerstopping treatment

■ Predictive: Quantitative PCR (a low viral load indicates a better

ment response) Genotypes 2 and 3 are associated with a better ment response than genotype 1

treat-■ Indications for treatment: Age 18–60, HCV viremia, elevated

inabil-■ Acute infection/needlestick prophylaxis: Currently not recommended.

■ Chronic HCV: Treatment is curative in up to 80% of genotype 2/3 cases

but is < 50% for genotype 1

Both HCV and HBV can cause

cryoglobulinemia and

glomerulonephritis.

■ Cryoglobulinemia: Treatment of acute flares includes plasmapheresis +/−

steroids Long-term effectiveness is seen with interferon plus ribavirin, and

data on rituximab appear promising

Autoimmune Hepatitis

Characterized by hypergammaglobulinemia, periportal hepatitis, and

autoim-mune markers Typically chronic, but 25% of cases are characterized by acute

onset and rare fulminant hepatic failure Prevalence depends on gender and

ethnicity; women are affected three times more often than men Incidence

among Northern American and European Caucasians is 1 in 100,000 Less

common in non-Caucasians; in Japan, incidence is 0.01 in 100,000 The risk

of cirrhosis is 17–82% at five years The main prognostic factors are severity of

inflammation/fibrosis on liver biopsy and HLA type Associated with other

■ Hepatomegaly, jaundice, splenomegaly (with or without cirrhosis)

■ Acute: Icteric sclera, arthritis, RUQ tenderness.

■ Chronic: Stigmata of cirrhosis (spider angiomata, palmar erythema,

gyne-comastia, ascites)

D IFFERENTIAL

Wilson’s disease, viral hepatitis (HBV, HCV), α1-antitrypsin deficiency,

he-mochromatosis, drug-induced hepatitis, alcoholic and nonalcoholic

steato-hepatitis

D IAGNOSIS

■ International Autoimmune Hepatitis Group (IAHG) criteria: A definite

or probable diagnosis of autoimmune hepatitis is made according to the

following criteria: (1) magnitude of hypergammaglobulinemia, (2)

autoan-tibody expression, and (3) certainty of exclusion of other diagnoses (see

Table 7.19)

■ Extrahepatic associations: Present in 10–50% of cases.

■ Frequent: Autoimmune thyroid disease, ulcerative colitis, synovitis.

■ Uncommon: RA, DM, CREST syndrome, vitiligo, alopecia.

T REATMENT

■ Treatment indications: Active symptoms, biochemical markers (elevated

ALT, AST, or gamma globulin), histologic markers (periportal hepatitis,

bridging necrosis) The best treatment responses are obtained in the

set-ting of active hepatic inflammation (high ALT)

■ Relative contraindications: Asymptomatic patients with mild biochemical

inflammation (AST < 3 times normal); cirrhosis without histologic

The decision to treat autoimmune hepatitis is dependent on the severity of hepatic inflammation, not hepatic dysfunction.

Autoimmune hepatitis is associated with a high rate of anti-HCV false positives, so the diagnosis must be confirmed

by checking a PCR assay for HCV viremia.

■ Steroid-sparing therapy: Lower-dose prednisone (30 mg QD); then taper

over 4–6 weeks in combination with azathioprine 50–75 mg QD

■ Treatment end points: Defined at the end of steroid taper.

■ Remission: No symptoms; AST < 2 times normal; normalization of

bilirubin and gamma globulin; biopsy with minimal inflammation

■ Treatment failure: Progressive symptoms; AST or bilirubin > 67% of

pretreatment values

■ Liver transplantation: Should be considered in the presence of

decom-pensated liver disease, severe inflammation, and necrosis on liver biopsywith treatment failure or no biochemical improvement during the first twoweeks of therapy

Drug-Induced Hepatitis

Ranges from subclinical disease with abnormal LFTs to fulminant hepaticfailure Accounts for 40% of acute hepatitis cases in U.S adults > 50 years ofage; for 25% of cases of fulminant hepatic failure; and for 5% of jaundicecases in hospitalized patients Drug-induced hepatitis can be characterized asintrinsic (direct toxic effect) or idiosyncratic (immunologically mediated in-jury) and as necroinflammatory (hepatocellular), cholestatic, or mixed Riskfactors include advanced age, female gender, use of an increasing number ofprescription drugs, underlying liver disease, renal insufficiency, and poor nu-trition

S YMPTOMS /E XAM

May present with constitutional symptoms, jaundice, RUQ pain, and pruritus.Often asymptomatic

1° sclerosing M > F AP > 1.5 times p-ANCA ERCP reveals Ulcerative colitis Liver transplant cholangitis ULN “beads on a in 70%.

a ULN = upper limit of normal; AP = alkaline phosphatase; ASMA = anti–smooth muscle antibody; anti-LKM antibody =

anti–liver/kidney microsome antibody.

Elevated serum LDH suggests

drug-induced hepatitis over

viral hepatitis.

Viral hepatitis, ischemic hepatitis, Wilson’s disease, α1-antitrypsin deficiency,

hemochromatosis, nonalcoholic steatohepatitis

D IAGNOSIS

Diagnose as follows (see also Table 7.20):

■ Exclude other causes: Obtain a liver ultrasound with duplex and hepatitis

serologies

■ History: Take a detailed drug history that includes dosage, duration, and

use of concurrent OTC, alternative, and recreational drugs

■ Labs: Elevated serum LDH; transaminases typically range from 2–4 times

normal (subclinical) to 10–100 times normal

■ Drug withdrawal: Most drug-induced hepatitis will improve with

discon-tinuation of the toxic agent

■ Liver biopsy: Most useful for excluding other etiologies Eosinophilic

in-flammatory infiltrate suggests drug-induced hepatitis; histologic patterns

can implicate drug classes

T REATMENT

■ Discontinue the implicated drug

■ Supportive care

■ Liver transplantation: Drug-induced fulminant hepatic failure has a low

likelihood of spontaneous recovery

Acetaminophen Toxicity

■ The most common cause of drug-induced hepatitis and drug-induced

ful-minant hepatic failure The toxic dose is > 4 g in nonalcoholics and > 2 g

in alcoholics, but much higher doses are frequently associated with

fulmi-nant hepatic failure

When ALT > 1000, consider

drug/toxic, ischemic, congestive, and viral hepatitis.

Relation to dosage Dose dependent Dose independent.

Frequency More common Less common.

Onset Hours to days after starting Weeks to months after

drug starting drug.

Toxicity Direct toxic effect Immune-mediated toxicity.

Implicated drugs Acetaminophen, carbon NSAIDs, INH,

tetrachloride, alcohol, sulfonamides, valproic

Amanita phalloides, acid, phenytoin, aflatoxins ketoconazole.

transami-■ Acetaminophen level: Predict toxicity with the Rumack-Matthew

nomogram (assesses acetaminophen concentration, time after tion, and risk for toxicity) Elevated levels precede transaminitis

inges-■ Prognostic factors predicting death or need for liver transplant:

Arte-rial blood pH < 7.3 or hepatic encephalopathy grade 3 or 4 with INR >6.5 and serum creatinine > 3.4 mg/dL

■ N-acetylcysteine 140 mg/kg PO; then 70 mg/kg q 4 h × 17 doses

■ Liver transplantation

Alcoholic Liver Disease

Alcohol accounts for 100,000 deaths per year in the United States, and 20% ofthese deaths are related to alcoholic liver disease, which carries a risk of pro-gressive liver disease Patients at risk include those exceeding the critical in-take threshold (80 g/day in men and 20 g/day in women), females, blacks,those with poor nutritional status, and those with HBV or HCV infection.The spectrum of disease includes fatty liver (steatosis), acute alcoholic hepati-

tis, and alcoholic (Lặnnec’s) cirrhosis.

S YMPTOMS

■ Steatosis: Asymptomatic or mild RUQ pain.

■ Acute alcoholic hepatitis: Fever, anorexia, RUQ pain, jaundice, nausea,

vomiting

■ Alcoholic cirrhosis: Patients may be asymptomatic or may present with

anorexia, fatigue, and ↓ libido Associated with an ↑ risk of variceal orrhage

hem-E XAM

■ Exam may reveal hepatomegaly, splenomegaly, cachexia, jaundice, spider

telangiectasias, Dupuytren’s contractures, parotid gland enlargement,

gynecomastia, and testicular atrophy

■ There are no symptoms specific to alcoholic liver disease

D IFFERENTIAL

Nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, autoimmunehepatitis, hemochromatosis, α1-antitrypsin deficiency, Wilson’s disease, viralhepatitis, toxic or drug-induced hepatitis

D IAGNOSIS

■ History of habitual alcohol consumption: The CAGE questionnaire is

sensitive for alcohol abuse

■ Alcoholic steatosis: Modest elevation of AST > ALT in a 2:1 ratio; liver

biopsy shows small (microvesicular) and large (macrovesicular) fat droplets

in the cytoplasm of hepatocytes

■ Alcoholic hepatitis: Marked leukocytosis, modest elevation of AST > ALT

in a 2:1 ratio, and markedly elevated serum bilirubin Liver biopsy shows

steatosis, hepatocellular necrosis, Mallory bodies (eosinophilic hyaline posits), ballooned hepatocytes, and lobular PMN inflammatory infiltrate.

de-Acetaminophen in modest

doses (e.g., < 2 g/day) is

much safer than NSAIDs for

patients with cirrhosis.

Alcoholic hepatitis is not a

prerequisite to alcoholic

cirrhosis.

■ Alcoholic cirrhosis: Liver biopsy shows micro- or macronodular cirrhosis

and perivenular fibrosis that is not usually seen in other types of cirrhosis

T REATMENT

■ The mainstays of treatment are alcohol abstinence and improved

nutri-tion Social support (e.g., AA) and medical therapy (e.g., disulfiram,

nal-trexone) can assist with abstinence

■ Alcoholic steatosis: Can resolve with abstinence and improved nutrition.

■ Alcoholic hepatitis:

■ Corticosteroids: Improve survival when discriminant function (DF) is

> 32 and there are no contraindications (active GI bleeding, active

in-fection, serum creatinine > 2.3) DF is a function of PT/INR and total

bilirubin

■ Other therapies under study: Medium-chain triglycerides and

pen-toxifylline Pentoxifylline has anti-TNF effects but is less effective than

corticosteroids when DF is > 32

■ Long-term therapy: Antioxidants, S-adenosylmethionine (SAMe),

sily-marin, vitamins A and E

■ Alcoholic cirrhosis: Hepatic function can significantly improve with

absti-nence and improved nutrition

■ Liver transplantation: Often precluded by active or recent alcohol abuse

or use Recidivism rates are high Most transplant centers require at least

six months of documented abstinence prior to listing for liver transplant

Nonalcoholic Fatty Liver Disease

The spectrum of disease ranges from benign steatosis (fatty liver) to

steatohep-atitis (hepatic inflammation) Prevalence in the United States is 15–25%

Steatohepatitis is found in 8–20% of morbidly obese individuals independent

of age Disease is generally benign and indolent but can progress to cirrhosis

in 15–20% of cases Risk factors for severe disease include female gender, age

> 45 years, body mass index (BMI) > 30, AST/ALT > 1, and type 2 DM

S YMPTOMS

Presents with fatigue, malaise, and, to a lesser extent, RUQ fullness or pain

Asymptomatic in > 50% of patients

E XAM

■ Hepatomegaly is common, but examination may be limited in the obese

■ Stigmata of chronic liver disease

D IFFERENTIAL

■ Alcoholic liver disease

■ Nutrition: TPN, kwashiorkor, rapid weight loss.

■ Drugs: Estrogens, corticosteroids, chloroquine.

■ Metabolic: Wilson’s disease, abetalipoproteinemia.

■ Iatrogenic: Weight reduction surgery with jejunoileal bypass, gastroplasty,

or small bowel resection

D IAGNOSIS

Diagnose as follows:

Exclude causes of liver disease, specifically alcoholic liver disease

Discriminant function (DF) measures the severity of alcoholic hepatitis A DF > 32

predicts one-month mortality

no contraindications (active GI bleeding, active infection, serum creatinine > 2.3).

Nonalcoholic fatty liver disease is the third most common cause of abnormal LFTs in adult outpatients after medication and alcohol.

■ The AST/ALT ratio ↑ with severity of liver disease, which is typical of

cirrhosis of all etiologies

■ BMI is an independent predictor of the degree of hepatocellular fatty tration

infil-■ Ultrasound or CT scan

■ Liver biopsy is the gold standard The grade of inflammation and stage offibrosis predict disease course and response to therapeutic intervention

T REATMENT

■ Gradual weight loss Rapid weight loss may ↑ inflammation and fibrosis

■ Treat hyperlipidemia and diabetes

■ No FDA-approved therapy is available

■ Therapeutic agents under study include metformin, rosiglitazone, deoxycholic acid,, and vitamin E

urso-M E TA B O L I C L I V E R D I S E A S E Hereditary Hemochromatosis

An autosomal-recessive disease Homozygote prevalence is 1 in 300 persons.

The most common genetic disease in Northern Europeans; the Caucasiancarrier rate is 1 in 10 Associated with a major mutation in chromosome 6, the

HFE gene Patients have a normal life expectancy if there is no cirrhosis and

the patient is adherent to treatment; survival is lower if the patient has sis at the time of diagnosis Cirrhosis with hereditary hemochromatosis car-

cirrho-ries a high risk of hepatocellular carcinoma (200 times that of the control ulation)

pop-S YMPTOMS

Arthritis (pseudogout), skin color change, RUQ pain, symptoms of chronicliver disease (fatigue, anorexia, muscle wasting), loss of libido, impotence anddysmenorrhea, heart failure, DM Often asymptomatic (10–25%)

E XAM

Hepatomegaly, skin hyperpigmentation (bronze skin), stigmata of chronicliver disease, hypogonadism

D IFFERENTIAL

■ Chronic liver diseases: HBV, HCV, alcoholic liver disease, nonalcoholic

fatty liver disease, Wilson’s disease, α1-antitrypsin deficiency, autoimmunehepatitis

■ 2° iron overload diseases: Homozygous α-thalassemia; multiple previous

blood transfusions

D IAGNOSIS

■ Suspect hereditary hemochromatosis with an unexplained high serum ritin or iron saturation even with normal LFTs.

fer-Normal LFTs do not exclude

nonalcoholic fatty liver

disease.

Screen for hemochromatosis

with fasting serum transferrin

saturation (TS) and ferritin; TS

> 45% with an elevated

ferritin suggests but does not

confirm the diagnosis.