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jaundice or abnormal liver enzymes🚧 施工中
jaundice or abnormal liver enzymes
Jason Alexander, MD
CHIEF COMPLAINT
PATIENT
Ms. B is a 56-year-old woman who comes to your office because her skin and eyes have been yellow for the past 2 weeks.
What is the differential diagnosis of jaundice? How would you frame the differential?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
The differential diagnosis of jaundice, or hyperbilirubinemia, is often organized pathophysiologically. It is helpful to review some basic physiology first.
A. Oxidation of the heme moiety of hemoglobin generates biliverdin, which is metabolized into unconjugated bilirubin, and then bound to albumin.
B. There are 3 steps in bilirubin metabolism in the liver (Figure 26-1):
Figure 26-1. Bilirubin metabolism and excretion.
1. Uptake: The unconjugated bilirubin-albumin complex reaches the hepatocyte; bilirubin dissociates from albumin and then enters the hepatocyte.
2. Conjugation: Unconjugated bilirubin and glucuronic acid combine to make conjugated bilirubin.
3. Excretion: The hepatocyte excretes conjugated bilirubin into the bile.
a. The rate-limiting step of bilirubin metabolism in the liver
b. If excretion is impaired, conjugated bilirubin enters the hepatic sinusoids and then the bloodstream.
C. Conjugated bilirubin in the bile is transported through the biliary ducts into the duodenum; it is not reabsorbed by the intestine.
1. Can be excreted unchanged in the stool
2. Can be converted to urobilinogen by colonic bacteria
a. Urobilinogen can be reabsorbed, entering the portal circulation.
b. Some is taken up by the liver and re-excreted into the bile.
c. Some bypasses the liver and is excreted by the kidney, thus appearing in the urine in small amounts.
d. Can be converted in the bowel to stercobilin rendering the stool brown.
D. Unconjugated bilirubin is not found in the urine because it is bound to albumin and cannot be filtered by the glomeruli.
E. Conjugated bilirubin is filtered and excreted in the urine when there is conjugated hyperbilirubinemia.
The first pivotal point in the differential diagnosis of hyperbilirubinemia is determining which kind of bilirubin is elevated.
Dark, tea-colored urine means the patient has conjugated hyperbilirubinemia.
Light stools, often described as “clay colored,” occur when extrahepatic obstruction prevents bilirubin from entering the intestine.
If the patient has unconjugated hyperbilirubinemia (> 50% of the bilirubin is unconjugated), use a pathophysiologic framework:
A. Increased bilirubin production
1. Hemolysis
2. Dyserythropoiesis
3. Extravasation of blood into tissues
B. Impaired hepatic bilirubin uptake
1. Heart failure
2. Sepsis
3. Drugs (rifampin, probenecid, gemfibrozil, atazanavir)
4. Fasting
5. Portosystemic shunts
C. Impaired bilirubin conjugation (decreased hepatic glucuronosyltransferase activity)
1. Hereditary
a. Gilbert syndrome
b. Crigler-Najjar syndrome
2. Acquired
a. Neonates
b. Hyperthyroidism
c. Ethinyl estradiol
d. Liver disease (causes mixed hyperbilirubinemia; usually predominantly conjugated)
e. Sepsis
Most patients with unconjugated hyperbilirubinemia have hemolysis, Gilbert syndrome, heart failure, sepsis, or very advanced cirrhosis.
Although many sources organize the differential diagnosis for conjugated hyperbilirubinemia (when > 50% is conjugated) using a pathophysiologic framework, a more practical, clinical approach uses the results of other liver biochemical tests first:
A. Normal liver enzymes (ALT, AST)
1. Sepsis or systemic infection
2. Rotor syndrome
3. Dubin-Johnson syndrome
B. Elevated liver enzymes
1. Hepatocellular pattern: transaminases more elevated than alkaline phosphatase, suggesting primary hepatocellular damage
a. Marked transaminase elevations (> 1000 units/L)
(1) Acute viral hepatitis
(2) Ischemic hepatitis
(3) Medication- or toxin-induced hepatitis
(4) Autoimmune hepatitis
(5) Acute bile duct obstruction
(6) Acute Budd-Chiari syndrome
b. Mild to moderate elevations (mild elevation: defined as < 5 times the upper limit of normal [approximately < 175–200 units/L])
(1) Alcoholic liver disease
(2) Medications/toxins
(3) Chronic hepatitis B or C
(4) Nonalcoholic fatty liver disease (NAFLD)
(5) Autoimmune hepatitis
(6) Hemochromatosis
(7) Wilson disease (in patients < 40 years old)
(8) Alpha-1-antitrypsin deficiency
2. Cholestatic pattern: alkaline phosphatase more elevated than transaminases, suggesting either intrahepatic or extrahepatic biliary obstruction
a. Extrahepatic cholestasis (bile duct obstruction)
(1) Common bile duct stone
(2) Benign stricture
(3) Benign polyp
(4) Malignancy (pancreatic cancer, cholangiocarcinoma, ampullary cancer)
(5) Periportal adenopathy
(6) Primary sclerosing cholangitis (affects both intrahepatic and extrahepatic ducts)
b. Intrahepatic cholestasis (primarily due to impaired excretion)
(1) Hepatitis (viral, alcoholic)
(2) Intrahepatic cholestasis of pregnancy
(3) Cirrhosis
(4) Medications and toxins
(5) Sepsis
(6) Total parenteral nutrition
(7) Postoperative jaundice
(8) Infiltrative diseases (amyloidosis, lymphoma, sarcoidosis, tuberculosis)
(9) Primary sclerosing cholangitis
(10) Primary biliary cirrhosis
Regardless of how you organize this differential, the first step is to determine whether the hyperbilirubinemia is primarily unconjugated or conjugated. The differential of unconjugated hyperbilirubinemia is relatively limited. If the hyperbilirubinemia is conjugated, the second step is to determine whether there is extrahepatic obstruction or intrinsic hepatocellular dysfunction due to 1 of many possible etiologies. Although other liver biochemical tests can serve as a guide, it is clear from the way the above differentials overlap that these tests are not very specific. Table 26-1 summarizes the commonly used liver tests. Figure 26-2 outlines the diagnostic approach to hyperbilirubinemia.
Table 26-1. Biochemical markers used to evaluate the liver.
Figure 26-2. Diagnostic approach to hyperbilirubinemia.
Ms. B also tells you she has dark urine, anorexia, and fatigue. She has no nausea, vomiting, abdominal pain, or fever. Ms. B’s physical exam shows scleral icterus and jaundice as well as hepatomegaly, with her liver edge palpable 7 cm below the costal margin. The liver extends across the midline, and the spleen tip is palpable. There is no abdominal tenderness or distention. There is no peripheral edema, and the rest of her exam is normal.
How reliable is the physical exam for detecting signs of liver disease?
A. Jaundice
1. Detectable on physical exam when total bilirubin is > 2.5–3.0 mg/dL.
Scleral icterus is detectable before jaundice of the skin.
2. For bilirubin > 3.0 mg/dL, sensitivity of physical exam is 78.4% and specificity is 68.8% (LR+ 2.5; LR–, 0.31).
3. For bilirubin > 15.0 mg/dL, sensitivity of physical exam is 96.4%.
B. Hepatomegaly
1. On ultrasound, the upper limit of normal for the cephalocaudad dimension of the liver is 13 cm.
2. While examiners are always correct when they report palpating the liver edge (LR+ = 233), a palpable liver edge is not a reliable sign of hepatomegaly (LR+, 2.0; LR–, 0.41) since the liver may be pushed caudally by enlarged lungs.
C. Splenomegaly
1. Percussion methods have poor test characteristics and are nondiagnostic.
2. Palpation of a spleen in a supine position is highly predictive of splenomegaly: LR+, 8.2; LR–, 0.41.
D. Ascites
1. The best 3 historical findings are
a. Increased abdominal girth (LR+, 4.1; LR−, 0.17)
b. Recent weight gain (LR+, 3.2; LR–, 0.42)
c. Ankle swelling (LR+, 2.80; LR−, 0.10)
2. The best physical exam findings are
a. Fluid wave (LR+, 5.3; LR−, 0.57)
b. Shifting dullness (LR+, 2.1; LR−, 0.4)
c. Proper physical exam technique must be used to obtain these LRs.
3. Ultrasonography can detect minimal ascites, far less than could ever be detected on physical exam.
Given the pivotal historical point (dark urine) and the physical exam findings of jaundice, hepatomegaly, and splenomegaly, you are confident that Ms. B has hyperbilirubinemia and suspect that it will be primarily conjugated. You obtain the following initial tests: total bilirubin, 13 mg/dL; direct bilirubin, 9.6 mg/dL; AST, 250 units/L; ALT, 113 units/L; alkaline phosphatase, 503 units/L; albumin, 2.8 g/dL; prothrombin time (PT), 15.4 s (control 11.1 s); WBC = 22,000 cells/mcL with 80% PMNs, 16% lymphocytes, and 4% monocytes. The platelet count is normal.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
The pattern of the biochemical abnormalities is the next pivotal point to consider. The combination of a substantially elevated alkaline phosphatase and moderately elevated transaminases is consistent with a cholestatic pattern due to either a disease causing intrahepatic cholestasis or to extrahepatic obstruction. Viral or alcoholic hepatitis, with or without cirrhosis, would be the most common diseases that cause both hepatocellular and cholestatic abnormalities; the AST being greater than the ALT is a pivotal finding that points toward alcoholic liver disease. The physical exam findings of hepatomegaly and splenomegaly both modestly increase the likelihood of chronic liver disease (LR+, 2.3 for hepatomegaly; 2.9 for splenomegaly). Extrahepatic obstruction must also be considered, since she could have an obstruction in addition to chronic liver disease. Cancer and stricture are more likely causes of painless jaundice than common bile duct stones. Pancreatic cancer is the most common malignancy that causes extrahepatic obstruction; cholangiocarcinoma and ampullary carcinoma are 2 other possibilities. Occasionally, obstruction is due to benign polyps in the biliary tree. Table 26-2 lists the differential diagnosis.
Table 26-2. Diagnostic hypotheses for Ms. B.
Ms. B had a blood transfusion in Latvia in 1996. She has no history of injection drug use, tattoos, or smoking, but she has consumed between 2 glasses and 1 bottle of wine daily for years. Her past medical history is notable only for Helicobacter pylori–positive gastric and duodenal ulcers 6 years ago, treated with eradication therapy. She is taking no medications.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Alcoholic Liver Disease (ALD)
Textbook Presentation
Patients may be asymptomatic, have incidentally discovered hepatomegaly or transaminase elevation, have symptoms of acute alcoholic hepatitis, or have manifestations of cirrhosis. Some or all of these symptoms may develop in an individual patient during the course of the disease.
Disease Highlights
A. Alcohol ingestion is the most important risk factor for ALD.
1. Beer and spirits are more associated with ALD than wine.
2. Drinking outside of meal time and binge drinking increase the risk.
B. Other risk factors include female sex, African-American and Hispanic ethnicity, obesity, and genetic factors.
C. ALD is more frequent and worse in patients with other chronic liver diseases, especially hepatitis C.
D. There are 3 histologic stages: steatosis, alcoholic steatohepatitis, and chronic hepatitis with fibrosis or cirrhosis.
1. Hepatic steatosis is generally asymptomatic.
a. 70% of patients have hepatomegaly
b. Occurs in up to 90% of patients who consistently consume > 6 drinks (60 g) per day
c. Potentiates liver damage from other insults, such as viral hepatitis or acetaminophen toxicity, and promotes obesity-related liver disease.
d. Usually completely reversible with abstinence from alcohol for 4–6 weeks
(1) Despite abstinence, cirrhosis will develop in 5–15% of patients with steatosis.
(2) Cirrhosis develops in 30% of those who continue to drink.
2. Alcoholic steatohepatitis occurs in 15–30% of patients with ALD.
a. Often presents acutely in the context of chronic liver disease
b. Symptoms often include fever, hepatomegaly, ascites, encephalopathy, AST:ALT ratio > 1.5, and leukocytosis, all in the context of heavy alcohol use.
c. Malnutrition is seen in 90% of patients.
d. Concomitant cirrhosis is found in > 50% of patients with alcoholic hepatitis.
e. 3-month mortality between 15% (mild alcoholic hepatitis) and 55% (severe alcoholic hepatitis)
f. Several tools have been developed to risk stratify patients with alcoholic hepatitis.
(1) The Modified Discriminant Function (mDF) = 4.6 × (patient PT − control PT) + serum bilirubin level: patients with a score ≥ 32 have a poor prognosis
(2) The Mayo End-stage Liver Disease (MELD) score incorporates the total bilirubin, international normalized ratio (INR), and serum creatinine (http://www.mayoclinic.org/meld/mayomodel7.html).
(a) A MELD score > 11 is similar to an mDF ≥ 32 in predicting mortality.
(b) A MELD score > 20 1 week after admission had a sensitivity of 91% and specificity 85% for identifying patients who will die within 30 days.
(3) The Glasgow Alcoholic Hepatitis Score (GAHS) includes age, WBC count, BUN, PT/INR, and total bilirubin (http://www.mdcalc.com/glasgow-alcoholic-hepatitis-score/): a score ≥ 9 is associated with a poor prognosis and has an accuracy of 81% in predicting 28-day mortality.
3. Cirrhosis (also see Chapter 17, Edema)
a. Increased risk in men who consume > 60–80 g/day and women who consume > 20 g/day of alcohol for ≥ 10 years. (One standard drink contains 14 g of alcohol.)
(1) Only 6–41% of such individuals develop cirrhosis
(2) Fibrosis develops in 40–60% of people who consume > 40–80 g/day for 25 years
b. In patients without any other chronic liver disease, 21 drinks/week in men and 7–14/week in women probably will not lead to ALD.
c. The prognosis of alcoholic cirrhosis varies, depending on whether the patient stops consuming alcohol.
(1) 5-year survival of 75% if patient becomes abstinent
(2) 5-year survival of 50% if patient continues to consume alcohol
(3) 5-year survival of 35% once complications of cirrhosis appear
Evidence-Based Diagnosis
A. ALD is diagnosed by documenting alcohol excess in the presence of liver disease.
B. Biomarkers such as GGT, AST, and ALT are not sensitive or specific enough to diagnose ALD; macrocytosis may be seen but is also insensitive.
C. Alcoholic steatosis is diagnosed by seeing fatty infiltration on imaging in patients with excessive alcohol consumption.
D. Alcoholic hepatitis is a clinical diagnosis.
1. Criteria used in randomized trials of therapy include history of excessive alcohol consumption; serum bilirubin > 4.5 mg/dL; AST < 500 units/L; ALT < 300 units/L; exclusion of acute viral, autoimmune, obstructive, or malignant liver disease.
2. Transaminases are elevated but generally < 6–7 times the upper limit of normal.
a. AST:ALT ratio > 2 in 70–80% of patients, with ratios > 3 being more specific
b. Another study showed mean ratio of 2.6 for patients with alcoholic liver disease, compared with mean of 0.9 for patients with nonalcoholic steatohepatitis; however, there was some overlap.
3. GGTP (gamma-glutamyl transpeptidase) is often elevated, and the GGTP/alkaline phosphatase ratio is often > 2.5.
4. Imaging (with ultrasonography or CT) is most helpful for ruling out other diagnoses; can variably see fatty infiltration, hepatomegaly, ascites, or cirrhosis.
5. Liver biopsy is the gold standard for diagnosis but is not always necessary.
E. Cirrhosis is diagnosed when portal hypertension is present or on biopsy (also see Chapter 17, Edema).
Treatment
A. Abstinence is the primary treatment for all forms of ALD.
B. Although the data are conflicting, current guidelines recommend that patients with severe alcoholic hepatitis, defined as an mDF score ≥ 32, should be treated with corticosteroids; pentoxifylline could be considered in patients intolerant of corticosteroids.
C. Patients with advanced disease or alcoholic hepatitis should be assessed for nutritional deficiencies and repleted as necessary.
MAKING A DIAGNOSIS
Ms. B’s transaminases are consistent with, but not diagnostic of, ALD. An imaging study is necessary not to rule in ALD but rather to exclude alternative diagnoses. As discussed in Chapter 3, Abdominal Pain, ultrasonography is the best first test to look for stones in the gallbladder, although the sensitivity is less for common bile duct stones. However, in this patient, pancreatic cancer or other malignancies are more likely causes of extrabiliary obstruction than stones. Although an abdominal CT scan is arguably a better first test to exclude these possibilities, an ultrasound is often obtained first in clinical practice due to its lower cost and lack of adverse effects. Tests for hepatitis are necessary in all patients with liver disease and are especially important in Ms. B because of her history of a blood transfusion.
Ms. B has an ultrasound that reveals no stones in the gallbladder and no common bile duct stones. An abdominal CT scan is obtained next, which shows an enlarged, nodular liver, moderate ascites, and a normal pancreas. Her ANA, hepatitis A IgM antibody, HBsAg, hepatitis B IgM core antibody, and hepatitis C antibody are all negative.
Have you crossed the diagnostic threshold for the leading hypothesis, alcoholic hepatitis? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Alternative Diagnosis: Pancreatic Cancer
Textbook Presentation
Patients with pancreatic cancer often have vague abdominal pain for weeks or months, followed by weight loss and perhaps the abrupt onset of painless jaundice.
Disease Highlights
A. > 90% of cases are ductal carcinomas; 60–70% are in the pancreatic head, 20–25% in the body or tail, and 10–20% involve the whole organ
B. Risk factors
1. Smoking (related in up to 20% of cases) and family history of pancreatic cancer (present in 7–10% of patients) are the most important risk factors.
2. Other risk factors include the following:
a. Family history of chronic pancreatitis, older age, male sex, African-American ethnic origin
b. Diabetes, obesity
c. Non-O blood group
d. Occupational exposures (chlorinated hydrocarbon solvents and nickel)
e. High fat diet; high meat/low vegetable diet
C. Clinical presentation
1. Symptoms are insidious and often present for more than 2 months; depression is the first symptom in 38–45% of patients.
2. Abdominal pain and weight loss are common presenting complaints, occurring in 80% and 85% of patients, respectively.
3. Back pain is prominent if splanchnic nerve or celiac plexus infiltration occurs.
4. Jaundice
a. 80% of patients with cancers in the head; more if mass is > 2 cm
b. Can occur when the cancer is in the body but is then due to liver metastases
c. Can be painless or associated with abdominal pain
5. Less common presentations include acute pancreatitis, malabsorption, migratory thrombophlebitis, and gastrointestinal bleeding.
6. Intraductal papillary mucinous neoplasms (IPMN), a potential precursor lesion of pancreatic ductal carcinomas, are increasingly being detected incidentally on abdominal imaging.
a. Histopathologic evaluation, usually through endoscopic ultrasound and fine-needle aspiration, in addition to imaging is critical for identifying high-risk lesions that can inform treatment decisions.
(1) IPMN lesions < 10 mm in size can be monitored with surveillance imaging.
(2) Those > 30 mm in size or with high-risk MRI characteristics should be biopsied.
(3) The approach to those between 10 mm and 30 mm in size is unclear.
b. If pancreatic cancer develops, the 5-year survival is ∼50%, which is much higher than ductal adenocarcinoma.
Evidence-Based Diagnosis
A. The first imaging study in most patients presenting with jaundice is an ultrasound.
1. Sensitivity, 75–89%; specificity, 90–99%
2. The sensitivity may be less in obese patients or with less experienced sonographers.
B. If the ultrasound shows a pancreatic mass, the next test should be a triphasic pancreatic-protocol multidetector CT.
1. Sensitivity, 86%; specificity, 90%; LR+, 8.6; LR–, 0.16
2. Sensitivity lower for cancers < 2 cm (77%) compared with those > 2 cm (89%)
3. Best test for determining potential resectability
C. If an initial ultrasound does not show a mass, pancreatic protocol CT, magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) should be done.
1. MRCP is noninvasive with similar sensitivity and specificity to pancreatic protocol CT.
2. EUS requires endoscopy but does not lead to as many complications as ERCP; sensitivity, 94%; specificity, 89%; LR+, 8.5; LR–, 0.06.
3. ERCP is invasive and has a sensitivity of only 50–60% for detecting pancreatic cancer, with a specificity of 94%; complications include pancreatitis and hemorrhage.
D. CA 19-9
1. For levels above 37 units/mL: sensitivity, 77%; specificity, 87%
2. For levels > 1000 units/mL, specificity is 94–100%.
Treatment
A. Complete resection is possible in ∼15% of patients; 5-year survival is still only 20–25%.
B. Palliative approach for patients with nonresectable cancer
1. Biliary diversion, either percutaneous or surgical
2. Radiation therapy for pain relief
3. Gemcitabine for improved quality of life but not increased survival
4. Median survival is 6 months.
CASE RESOLUTION
With an LR– of 0.16, a normal CT scan does not always rule out pancreatic cancer. However, in this patient, given that her CT scan shows evidence of advanced liver disease (a more likely diagnosis for her), it is not necessary to do further imaging studies. The other active alternative, chronic hepatitis, is ruled out by her negative serologies. These test results, combined with her alcohol intake history, makes ALD the most likely diagnosis. At this point, some clinicians would proceed with treatment for alcoholic hepatitis, while others would confirm the diagnosis and, for prognostic purposes, establish the presence or absence of cirrhosis with a liver biopsy.
Her liver biopsy showed acute alcoholic hepatitis with cirrhosis. Because her mDF was > 32, she was treated with prednisolone. She was also advised to abstain from alcohol. She completed the course of prednisolone and has remained abstinent. Several weeks later, her bilirubin was normal and she felt well.
CHIEF COMPLAINT
PATIENT
Mr. R is a 24-year-old graduate student with no past medical history who comes to see you because his girlfriend thought his eyes looked yellow yesterday. He has felt tired and a bit queasy for the last couple of weeks but thought he was just overworked and anxious. He has had some aching pain in the right upper quadrant and epigastrium, not related to eating or bowel movements. He has had no fevers, chills, or sweats. He has noticed dark urine for 1 or 2 days but attributed it to not drinking enough.
On physical exam, he appears tired. He has scleral icterus; his liver is palpable 2 cm below the costal margin and is mildly tender. The spleen is not palpable, and the rest of his abdomen is nontender and nondistended. He has no edema, and the rest of his exam is normal.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
The differential diagnosis for fatigue, nausea, and vague abdominal pain is broad, but the pivotal findings of scleral icterus and tender hepatomegaly point toward a hepatic source.
Mr. R’s clinical picture is consistent with that of the majority of patients with viral hepatitis: a history of anorexia, malaise, and nausea, and a physical exam showing hepatomegaly, hepatic tenderness, or both. Hepatitis A is the most frequent cause of acute viral hepatitis; hepatitis C is the second most frequent but is usually asymptomatic acutely. Hepatitis B can also present acutely. By virtue of being common, alcoholic hepatitis is another active alternative diagnosis, and the presentation can mimic that of viral hepatitis. Biliary obstruction is always a consideration in patients with jaundice, but the prodrome and type of abdominal pain are not typical. Table 26-3 lists the differential diagnosis.
Table 26-3. Diagnostic hypotheses for Mr. R.
He has no past medical history and takes no medications; he does not smoke or use illicit drugs. He drinks 1–2 beers most weeks, and occasionally shares a bottle of wine with friends. He has never had a blood transfusion or a tattoo, and has had only 1 sexual partner. He enjoys trying different restaurants, and frequently eats sushi and ceviche. Initial laboratory tests include the following: total bilirubin, 6.5 mg/dL; conjugated bilirubin, 4 mg/dL; ALT, 1835 units/L; AST, 1522 units/L; alkaline phosphatase, 175 units/L; WBC, 9800 cells/mcL (normal differential); Hb, 14.5 g/dL; HCT, 44%.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Pivotal points in Mr. R’s lab tests include the following: he has a conjugated hyperbilirubinemia with a hepatocellular pattern, marked elevation of the transaminases, and the ALT is greater than the AST. This pattern is consistent with viral hepatitis. Exploring his history, he does not have clear risk factors for hepatitis B or C, but does have potential exposure to contaminated food, suggesting possible hepatitis A.
Leading Hypothesis: Hepatitis A
Textbook Presentation
The classic presentation is the gradual onset of malaise, nausea, anorexia, and right upper quadrant pain, followed by jaundice.
Disease Highlights
A. Prevalence: Accounts for approximately half of cases of viral hepatitis in the United States.
B. Clinical manifestations
1. Symptoms develop in 70–80% of adults, compared with < 30% of children under the age of 6.
2. Average incubation period is 28 days (range 15–50 days), followed by prodromal symptoms of fatigue, malaise, nausea, vomiting, anorexia, fever, and right upper pain; about 1 week later, jaundice appears.
3. 70% of patients have jaundice, and 80% have hepatomegaly.
4. Other physical findings include splenomegaly, cervical lymphadenopathy, rash, arthritis, and leukocytoclastic vasculitis.
5. Uncommon extrahepatic manifestations include optic neuritis, transverse myelitis, thrombocytopenia, and aplastic anemia.
C. Transmission
1. Fecal-oral transmission, either sporadically or in an epidemic form
a. Contaminated water, shellfish, frozen strawberries, etc.
b. Contamination from infected restaurant worker
c. No specific exposure history in 55% of cases
2. No maternal-fetal transmission
D. Clinical course
1. Generally self-limited, with rare cases of fulminant hepatic failure (0.015–0.5% of patients with hepatitis A)
a. Fulminant course is more common in patients with underlying hepatitis C or other chronic liver diseases.
b. 1.1% fatality rate in adults > age 40
2. 85% of patients fully recover in 3 months, and nearly 100% by 6 months
3. Transaminases normalize more rapidly than serum bilirubin.
E. Prevention
1. Vaccination is available for preexposure prophylaxis.
a. Immunity develops within 4 weeks in 90% of patients and within 26 weeks in 100% of patients.
b. A second dose given 6–12 months later provides persistent immunity.
2. Can use immune serum globulin with vaccination for postexposure prophylaxis.
a. For otherwise healthy patients between ages 12 months and 40 years, only vaccination is recommended; immune serum globulin can still be considered.
b. For patients < 12 months, > 40 years, or any age who are immunocompromised, such as those with chronic liver disease, immune serum globulin should be administered.
c. Immune globulin is 69–89% effective in preventing symptomatic illness when used within 2 weeks of exposure.
d. A randomized trial comparing vaccination with immune globulin given within 14 days of exposure found that hepatitis A developed in 4.4% of vaccine recipients and 3.3% of immune globulin recipients (relative risk = 1.35 (95% confidence interval [CI], 0.70 to 2.67).
Evidence-Based Diagnosis
A. Liver biochemical tests
1. ALT and AST are generally over 1000 units/L, and may be as high as 10,000 units/L; ALT is generally > AST.
2. Bilirubin is commonly > 10 mg/dL.
3. Alkaline phosphatase is usually modestly elevated.
B. Antibody tests (Figure 26-3)
Figure 26-3. Natural history of hepatitis A symptoms and antibodies. ALT, alanine aminotransferase; HAV, hepatitis A virus. (Reproduced with permission from Frauci AS, Kasper DL, Braunwald E, et al: Harrison’s Principles of Internal Medicine, 18th ed. New York, NY: McGraw-Hill Education; 2011.)
1. Serum IgM anti-HAV detects acute illness, being positive even before the onset of symptoms and remaining positive for 4–6 months.
2. LR+ 99; LR−, 0.01
3. Serum IgG anti-HAV appears in the convalescent phase of the disease and remains positive for decades.
Treatment
A. Supportive therapy: rest, oral hydration, and antiemetic medications as needed
B. Admit if INR is elevated or patient is unable to hydrate orally.
C. Liver transplant if fulminant hepatitis and liver failure occur
MAKING A DIAGNOSIS
Considering the hepatocellular pattern of Mr. R’s liver test abnormalities, the acute onset of his symptoms, and his lack of signs of chronic liver disease, the pretest probability for some form of viral hepatitis is so high that it is not necessary to consider other diagnoses at this point. Although Mr. R’s history of food exposure suggests hepatitis A, it is generally necessary to test for all 3 of the primary hepatitis viruses since the exposure history for both hepatitis B and C is often unclear.
His hepatitis A IgM antibody is positive, with negative HBsAg, IgM anti-HBc, and anti-HCV.
Have you crossed a diagnostic threshold for the leading hypothesis, acute hepatitis A? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Alternative Diagnosis: Acute Hepatitis B
Textbook Presentation
The classic presentation is the gradual onset of malaise, nausea, anorexia, and right upper quadrant pain followed by jaundice. Hepatitis B is often subclinical.
Disease Highlights
A. Prevalence of hepatitis B virus (HBV) carriers
1. About 5% worldwide, with substantial geographic variation
a. 0.1–2% (low prevalence) in the United States, Canada, Japan, and Western Europe
b. 2–8% (medium prevalence) in Mediterranean countries, central Asia, the Middle East, and Latin and South America
c. 10–20% (high prevalence) in Southeast Asia, China, and sub-Saharan Africa
B. Clinical manifestations
1. 70% of adult patients have subclinical infection or are anicteric; 30% of patients have icteric hepatitis
2. Incubation period is 1–4 months.
3. Symptoms are similar to those of hepatitis A, but serum sickness–like syndrome can be part of the prodrome (fever, urticarial rash, arthralgias).
4. Fulminant hepatic failure occurs in 0.1–0.5% of patients, with a mortality rate of 80% without liver transplant.
C. Transmission
1. In high prevalence areas, transmission is primarily perinatal, occurring in 90% of babies born to hepatitis B envelope antigen (HBeAg)-positive mothers and in 10–20% born to HBeAg-negative mothers.
2. In medium prevalence areas, most infections occur from childhood exposure to contaminated household objects, via minor breaks in the skin or mucous membranes.
3. In low prevalence areas, transmission is most often sexual, via percutaneous inoculation (eg, injection drug use, accidental needlestick, tattooing, body piercing, acupuncture), or from contaminated blood transfusion or medical equipment (such as dialysis equipment).
D. Prevention of hepatitis B
1. Vaccination for preexposure prophylaxis
2. Vaccination and HB immune globulin within 12 hours for perinatal exposure and within 1 week for other postexposure prophylaxis (percutaneous, mucosal, or sexual)
3. Vaccinated individuals will have positive hepatitis B surface antibody (anti-HBs) tests.
Evidence-Based Diagnosis
A. Liver biochemical tests: similar to hepatitis A
1. Transaminases normalize in 1–4 months if acute infection resolves.
2. Elevation of ALT for > 6 months indicates progression to chronic hepatitis.
B. Acute infection is diagnosed by the presence of hepatitis B surface antigen (HBsAg) and IgM hepatitis B core antibody (IgM anti-HBc).
1. HBsAg appears 1–6 weeks prior to symptoms or elevations of transaminases (Figure 26-4).
Figure 26-4. Natural history of acute hepatitis B infections. (Reproduced with permission from Frauci AS, Kasper DL, Braunwald E, et al: Harrison’s Principles of Internal Medicine, 18th ed. New York, NY: McGraw-Hill Education; 2011.)
a. Should be present in patients with acute symptoms
b. Should clear in 4–6 months, although small amounts of viral DNA can be detected in serum and mononuclear cells for years after seroclearance
2. IgM anti-HBc appears 1–2 weeks after HBsAg.
a. The only marker of acute infection detectable during the “window period,” the several weeks to months between the disappearance of HBsAg and the appearance of anti-HBs.
b. Persists for up to 6 months after HBsAg is cleared
c. LR+ 27; LR−, 0.2
C. Previous infection is diagnosed by the presence of anti-HBs and IgG anti-HBc.
1. Anti-HBs appears weeks to months after disappearance of HBsAg
2. Anti-HBs test characteristics: LR+ 45; LR−, 0.1
D. HBeAg and anti-HBe historically used to show viral replication and infectivity but have largely been replaced by HBV DNA testing.
Treatment
A. Supportive therapy: rest, oral hydration, and antiemetic medications as needed
B. Admit if INR is elevated or patient is unable to hydrate orally.
C. Antiviral therapy is used for chronic infection and antiviral therapy or liver transplant can be used for fulminant hepatitis.
Alternative Diagnosis: Chronic Hepatitis B
Textbook Presentation
Manifestations can range from asymptomatic, to isolated fatigue, to cirrhosis with portal hypertension. There is often no history of clinical acute hepatitis B.
Disease Highlights
A. Defined as detection of HBsAg on 2 occasions measured at least 6 months apart
B. Occurs when the hepatitis B–specific CD4 and CD8 response is insufficient
C. Risk of progression from acute to chronic hepatitis B varies, depending on the patient
1. < 1% when the acute infection is acquired by an immunocompetent adult
2. 90% when the infection is acquired perinatally
3. 20% when the infection is acquired during childhood
D. Two-thirds of patients are asymptomatic.
E. 10–20% have extrahepatic findings (eg, polyarteritis nodosa, glomerular disease)
F. There are 4 phases of chronic HBV (Figure 26-5), categorized by the activity of the infection, as defined by levels of viral DNA, degree of transaminitis, and presence or absence of HBe antigen and antibody. (HBe antigen is a secretory protein considered to be a marker of HBV replication and infectivity. The presence of HBeAg usually indicates high levels of viral DNA and rates of transmission.)
1. The immune tolerant phase occurs when the infection is acquired perinatally.
2. Infections acquired later in life begin in the immune clearance phase, characterized by intermittent flares in up to 25% of patients per year; 10–20% of patients per year seroconvert from HBeAg positive to HBeAg negative and become HBeAb positive.
3. Most patients who seroconvert enter a lifelong inactive state; however, 20–30% revert to HBeAg positive or develop HBeAg negative chronic hepatitis.
G. Risk factors for progression from chronic hepatitis to cirrhosis include high viral DNA levels, longer duration of the immune clearance phase, male sex, increasing age, HBeAg positivity, genotype C, concurrent hepatitis C or HIV infection, severe inflammatory histology.
H. Hepatitis B cirrhosis leads to hepatic decompensation in 15–20% of patients over 5 years.
1. 5-year survival rate is 80–85% in patients with compensated cirrhosis and 30–50% in those with decompensated cirrhosis.
2. Each year, hepatocellular carcinoma develops in 2–3% of HBsAg-positive patients.
I. Screening guidelines
1. The US Preventive Services Task Force recommends screening for patients at high risk for hepatitis B
2. Patients at high risk for hepatitis B include
a. Patients coinfected with HIV and/or hepatitis C
b. Injection drug users
c. Household members and sexual partners of anyone with chronic hepatitis B
d. Men who have sex with men
e. Healthcare workers
f. Patients undergoing hemodialysis
g. Patients who are incarcerated
J. Patients who are at high risk for hepatitis B and screen negative should be offered vaccination.
Evidence-Based Diagnosis
A. HBsAg is characteristically positive.
B. See Figure 26-5 for patterns of HBeAg, HBV DNA, and ALT in different phases.
Figure 26-5. Natural phases of chronic HBV infection. anti-HBe, hepatitis B envelope antibody; HBV, hepatitis B virus; HBeAg, hepatitis B envelop antigen; HBsAg, hepatitis B surface antigen. (Reproduced with permission from Trépo C, Chan HL, Lok A: Hepatitis B virus infection, Lancet. 2014 Dec 6;384(9959):2053–2063.)
C. See Table 26-4 for interpretation of hepatitis B serologies.
Table 26-4. Interpretation of hepatitis B tests.
Treatment
A. The goals of treatment include suppression of viral DNA levels, HBeAg seroconversion, stopping or reducing hepatic inflammation and necrosis, and preventing progression to cirrhosis.
B. Current treatment options include nucleos(t)ide analogs, such as entecavir and tenofovir; and pegylated interferon alfa therapy. In most cases, nucleos(t)ide analogs are considered first-line therapy.
C. Patients should be screened for hepatocellular carcinoma every 6 months with ultrasonography.
Alternative Diagnosis: Hepatitis C
Textbook Presentation
Most patients are asymptomatic, with jaundice developing in < 25%. When present, symptoms are similar to those of other viral hepatitides and last 2–12 weeks.
Disease Highlights
A. Accounts for about 15% of cases of acute hepatitis; the most common cause of chronic hepatitis in the United States
B. Prevalence and transmission rates
1. Overall prevalence in the United States is 1%.
a. 2.6% prevalence in the general population born between 1945 and 1965
b. Largest risk factor is history of injection drug use; of patients with hepatitis C, 51% have prior history of injection drug use.
c. 1–5% in needlestick exposures and monogamous partners of infected persons
d. 10% in recipients of blood transfusions prior to 1992
2. Transmission
a. Since 1992, rarely acquired from blood transfusion in developed countries but contaminated blood still common in undeveloped countries
b. Now, hepatitis C is primarily transmitted through injection drug use, with occasional cases due to ear or body piercing, sex with an injection drug user, or accidental needlesticks.
c. Household contacts are rarely infected.
d. Transmission between monogamous partners is < 1%/year; risk of sexual transmission is higher in men who have sex with men, if the index carrier also has HIV, or if there are multiple partners.
e. Perinatal transmission occurs in 4–7% of cases; risk for transmission increases 4- to 5-fold if the mother has both hepatitis C and HIV.
f. 15–30% of patients report no risk factors
C. Clinical course
1. Jaundice develops in only 10–20% of symptomatic patients.
2. Fulminant hepatitis is rare.
3. Extrahepatic manifestations are common, being found in about 75% of patients.
a. Fatigue, arthralgias, paresthesias, myalgias, pruritus, and sicca syndrome are found in > 10% of patients.
b. Vasculitis secondary to cryoglobulinemia is found in 1% of patients, although cryoglobulinemia is present in about 40%.
c. Depression and anxiety are more common than in uninfected persons.
4. 74–86% of patients have detectable HCV RNA at 6 months and therefore have chronic hepatitis C.
5. Spontaneous clearance is more likely to occur in females, those infected with genotype 3, whites, and those with a low peak viral load.
D. Chronic hepatitis C
1. Liver histology ranges from no fibrosis, to varying degrees of fibrosis, to cirrhosis; there are several scoring systems in use.
2. There is no correlation between ALT levels and liver histology.
3. Noninvasive testing or liver biopsy is indicated in many patients to guide treatment decisions (see Chapter 17, Edema for discussion of noninvasive methods to predict fibrosis and cirrhosis); the complication rate for liver biopsy is 1–5%.
4. Cirrhosis develops in 7–18% of patients after 20 years of infection.
a. Liver histology is the best predictor of progression to cirrhosis.
b. Other predictors of progression to cirrhosis include
(1) Age at infection (> 40 years of age → more progression)
(2) Longer duration of infection
(3) Consumption of alcohol > 50 g/day
(4) HIV or HBV coinfection
(5) Male sex
(6) Higher ALT
(7) Baseline fibrosis
c. Hepatocellular carcinoma develops in 1–3% of cirrhotic patients per year.
E. Prevention
1. No vaccine available
2. No role for immunoglobulin
F. Screening guidelines
1. Centers for Disease Control and Prevention and US Preventive Services Task Force recommend 1 time screening for all persons born between 1945 and 1965 as well as risk factor–based screening
2. Risk factor–based screening includes
a. History of injection drug use
b. Receipt of blood products prior to 1992
c. Long-term hemodialysis
d. Exposure to known HCV-positive blood (needlestick or mucosal exposure in health care workers)
e. HIV infection
f. Child of a HCV-positive woman
g. History of multiple sex partners or sexually transmitted infections
Evidence-Based Diagnosis
A. Anti-HCV antibody tests (enzyme immunoassays)
1. HCV antibodies generally detectable within 8–12 weeks of acquiring the infection.
2. Sensitivity, 94–100%; specificity, 97–98%; LR+, 31–49; LR–, 0.01–0.06
3. False-positive results do occur in low prevalence screening populations, with positive predictive values as low as 39%.
4. False-negative results can occur in immunocompromised patients, such as organ transplant recipients, HIV-infected patients, hemodialysis patients, or those with hypogammaglobulinemia.
5. Unlike hepatitis A and B, the presence of antibodies does not indicate clearance of infection; patients with positive anti-HCV antibodies must be evaluated for ongoing infection.
B. Quantitative HCV RNA tests (polymerase chain reaction and transcription-mediated amplification)
1. Lower limit of detection using current methods is 10–50 international units/mL.
2. Sensitivity, 96%; specificity, 99%; LR+, 96; LR–, 0.04
3. Levels do not correlate with liver injury, duration of infection, or disease severity.
C. Genotype testing
1. Used for prediction of response to treatment, choice of treatment duration, and choice of therapy.
2. Genotypes do not change, so this test needs to be done only once.
3. In the United States, 71.5% of cases are from genotype 1, 13.5% from genotype 2, 5.5% from genotype 3, and 1.1% from genotype 4.
D. Choosing and interpreting hepatitis C tests
1. American Association for the Study of Liver Disease Guidelines for testing:
a. First, test for anti-HCV antibodies in patients in whom acute or chronic hepatitis C is suspected.
b. Test for HCV RNA in patients with (1) a positive antibody test; (2) unexplained liver disease whose antibody test is negative and who are immunocompromised or in whom acute HCV infection is suspected.
2. Table 26-5 summarizes the interpretation of hepatitis C tests.
Table 26-5. Interpretation of HCV tests.
Treatment
A. Goals of treatment
1. Prevention of cirrhosis and its complications
2. Reduction of extrahepatic manifestations
3. Reduction of transmission
B. A sustained virologic response is defined as nondetectable HCV RNA 6 months after completion of therapy.
C. Direct-acting antiviral drugs such as ledipasvir/sofosbuvir have revolutionized treatment and now supersede prior regimens of pegylated interferon and ribavirin.
CASE RESOLUTION
Mr. R clearly has acute hepatitis A, presumably from contaminated food. Although he is nauseated, he is able to drink adequate fluid. His INR is normal at 1.1. You recommend rest and oral hydration for Mr. R, and vaccination for his girlfriend. He feels much better when he returns 1 month later.
The best test of the liver’s synthetic function is the PT. It is important to check the INR in all patients with hepatitis to look for signs of liver failure.
Concomitant infection with HIV, in addition to the other viral hepatitides, should be ruled out in any patient diagnosed with hepatitis A, B, or C. In patients diagnosed with hepatitis B specifically, hepatitis D coinfection should also be excluded.
CHIEF COMPLAINT
PATIENT
Ms. H is a 40-year-old woman with unexpected transaminase abnormalities.
What is the differential diagnosis of mild asymptomatic transaminase elevations? How would you frame the differential?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
Most patients with asymptomatic transaminase elevations have mild or moderate elevations; it is very unusual for patients with marked elevations to be asymptomatic. Therefore, the diagnostic thinking should focus on chronic diseases. The basic framework separates hepatic from nonhepatic causes.
A. Hepatic causes
1. Marked elevations (> 1000 units/L)
a. Acute viral hepatitis
b. Ischemic hepatitis
c. Medication- or toxin-induced hepatitis
d. Autoimmune hepatitis
e. Acute bile duct obstruction
f. Acute Budd-Chiari syndrome
2. Mild to moderate elevations
a. ALD
b. Medications/toxins
c. Chronic hepatitis B or C
d. NAFLD
e. Autoimmune hepatitis
f. Hemochromatosis
g. Wilson disease (in patients < 40 years old)
h. Alpha-1-antitrypsin deficiency
B. Nonhepatic causes
1. Celiac disease
2. Hyperthyroidism
3. Inherited disorders of muscle metabolism or acquired muscle disease (AST elevation only)
4. Strenuous exercise (AST elevation only)
Ms. H comes in for a routine new patient visit. She feels fine. Her past medical history is notable for type 2 diabetes mellitus and hypertension. Her medications include metformin, atorvastatin, hydrochlorothiazide, and lisinopril. She does not smoke and has a glass of wine about twice per month. She has no history of blood transfusions or injection drug use. Her physical exam shows a BP of 125/80 mm Hg, pulse of 80 bpm, RR of 16 breaths per minute, weight 230 lbs, and height 5 ft 9 in (BMI = 34.0). Pulmonary, cardiac, and abdominal exams are all normal.
She shows you blood test results from a recent health fair at work: creatinine, 0.9 mg/dL; HbA1C, 6.8%; LDL, 95 mg/dL; platelet count, 272/mcL; bilirubin, 0.8 mg/dL; AST, 85 units/L; ALT, 92 units/L; albumin, 4.0 g/dL; and a normal alkaline phosphatase. She reports she was told a few months ago that 1 of her liver tests was a little abnormal. No one in her family has had liver disease, but her mother has thyroid disease. She does recall taking several acetaminophen tablets in the days prior to the recent blood test.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
In the absence of an obvious nonhepatic cause of liver enzyme elevations, the initial approach is to focus on the hepatic causes. The prevalence of the liver diseases in the differential diagnosis varies widely, depending on the population studied. For example, in a study of over 19,000 young, healthy military recruits, of whom 99 had enzyme elevations, only 11 were found to have any liver disease (4 had hepatitis B, 4 had hepatitis C, 2 had autoimmune hepatitis, 1 had cholelithiasis). A study of 100 blood donors with elevated enzymes found that 48% had ALD, 22% had NAFLD, and 17% had hepatitis C. In another study, patients with elevated enzymes in whom a diagnosis could not be made by history or blood tests underwent liver biopsy; NAFLD was found in over 50% of them.
Pivotal points in Ms. H’s presentation include that the transaminase abnormalities are mild and probably chronic. The key findings in the history and physical exam are the patient’s diabetes and elevated body mass index (BMI). NAFLD is extremely common in obese, diabetic patients, so Ms. H is at high risk for this disease. She has no specific risk factors for viral hepatitis, but often the exposure history is unclear and these diagnoses cannot be ruled out without further testing. Her alcohol intake is minimal, but sometimes even small amounts of alcohol can cause liver enzyme elevations. Additionally, other drug and toxin exposures always should be considered. Even therapeutic doses of acetaminophen can cause transaminitis; in 1 study, 50% of patients taking 4 g of acetaminophen daily developed transaminases > 2 times the upper limit of normal. Mild transaminase elevations are seen in 0.5–3% of patients taking statins (it is not necessary to stop the statin in such cases, and the FDA no longer recommends routine testing after obtaining a baseline at the start of therapy). Finally, her family history of thyroid disease, presumably autoimmune, increases the likelihood of autoimmune hepatitis or hyperthyroidism. Hemochromatosis can also present with liver enzyme abnormalities and diabetes mellitus. Table 26-6 lists the differential diagnosis.
Table 26-6. Diagnostic hypotheses for Ms. H.
Ms. H abstains from alcohol and stops taking any acetaminophen and atorvastatin for 2 weeks. Repeat liver enzymes show AST, 90 units/L, and ALT, 95 units/L. Her TSH is normal. Her grandparents emigrated from Northern Europe.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: NAFLD
Textbook Presentation
Patients are often asymptomatic but sometimes complain of vague right upper quadrant discomfort. It is common to identify patients by finding hepatomegaly on exam or asymptomatic transaminase elevations.
Disease Highlights
A. The definition of NAFLD is evidence of excessive fat in the liver, either by imaging or biopsy, in the absence of causes of secondary hepatic fat accumulation.
B. Secondary causes of excessive fat in the liver include
1. Significant alcohol use (> 14 drinks/week for women, > 21 for men)
2. Wilson disease
3. Jejunoileal bypass
4. Prolonged total parenteral nutrition
5. Protein-calorie malnutrition
6. Medications
a. Methotrexate
b. Amiodarone
c. Estrogens
d. Corticosteroids
e. Aspirin
f. Cocaine
g. Antiretroviral agents
C. Patients with NAFLD have steatosis, either with or without inflammation.
1. In simple steatosis (nonalcoholic fatty liver [NAFL]), there is no liver injury and the risk of progression to cirrhosis is < 4%.
2. Steatosis plus inflammation, with or without fibrosis, is called nonalcoholic steatohepatitis (NASH), which is a histologic diagnosis.
a. Up to 21% of patients with NASH and fibrosis have regression of fibrosis.
b. Up to 40% progress to more advanced fibrosis or cirrhosis
c. The strongest predictor of progression is the degree of inflammation on the first biopsy.
d. Annual risk of hepatocellular carcinoma 1–2%
3. Decompensated cirrhosis develops over 10 years in 45% of patients.
4. The risk of hepatocellular carcinoma in patients with NAFLD cirrhosis is less than that of patients with hepatitis C cirrhosis.
D. NAFLD can coexist with other chronic liver diseases.
E. Epidemiology
1. Risk factors include
a. The metabolic syndrome
b. Obesity
c. Type 2 diabetes mellitus
d. Insulin resistance
e. Hyperlipidemia
f. Family history of NAFLD
2. Prevalence varies based on population studied.
a. Worldwide prevalence is approximately 25%, higher in the Middle East and South Asia; NASH prevalence 3–5%
b. In patients with NAFLD in North America, 80% are obese, 25% have diabetes, and 83% have hyperlipidemia.
c. Found in > 95% patients undergoing bariatric surgery and 50% of patients attending lipid clinics
d. Second most common reason for liver transplant and will likely overtake hepatitis C in the near future
3. Most common cause of abnormal liver test results in the United States.
Evidence-Based Diagnosis
A. Blood tests
1. Transaminase elevation is usually < 400 units/L, with ALT > AST; in advanced fibrosis or cirrhosis, AST may be > ALT.
2. Serum ferritin is elevated in 60% of patients but is rarely > 1000 mcg/L.
3. Alkaline phosphatase is elevated in 30% of patients.
B. Imaging can detect steatosis when it replaces more than 30% of the liver volume; it cannot distinguish NAFL from NASH.
1. Ultrasonography
a. Sensitivity, 82–100%; specificity, ∼95% %
b. LR+, 18.2; LR–, 0.09
2. CT scan
a. Similar sensitivity and specificity to ultrasonography
b. However, more expensive and patient is exposed to radiation
3. MRI
a. Sensitivity, ∼95%; specificity, ∼95%
b. LR+, 19; LR–, 0.05
c. Higher sensitivity and specificity for detecting steatosis > 5% of the liver compared to ultrasonography and CT
C. Liver biopsy is the gold standard for diagnosis and staging.
1. NASH is missed in 27% of single biopsies.
2. Test characteristics of a single biopsy for the diagnosis of NASH
a. Sensitivity, 73%; specificity, 92%
b. LR+, 8.6; LR–, 0.3
3. Advanced fibrosis is less often missed: LR+, 7.7; LR–, 0.16
D. Liver biopsy should be considered when it is necessary to exclude other causes of chronic liver disease and in patients with a high risk of having NASH and advanced fibrosis.
1. The NAFLD Fibrosis Score is used to identify high-risk patients.
a. Need to know age, BMI, diabetes status, ALT, AST, albumin, and platelet count
b. Online calculator: http://nafldscore.com/
c. A high score (> 0.676) significantly increases the likelihood of advanced fibrosis (LR+, 16.5); low and intermediate scores are not as helpful.
2. Patients with the metabolic syndrome are also considered high risk.
E. Other modalities for noninvasively quantifying hepatic fibrosis include transient elastography and magnetic resonance elastography.
It is necessary to rule out other causes of liver disease listed in the above differential before diagnosing NAFLD.
Treatment
A. Weight loss can improve both steatosis and inflammation.
B. Exercise may improve steatosis independent of weight loss.
C. Diabetes and hyperlipidemia should be optimally treated.
D. Metformin has been studied and is not effective.
E. Vitamin E has been shown to improve histology in nondiabetic adults with biopsy proven NASH.
F. Pioglitazone is effective in reducing inflammation but its effect on fibrosis is uncertain; the long-term safety and efficacy are not established.
MAKING A DIAGNOSIS
You should take a stepwise approach to evaluating asymptomatic liver enzyme abnormalities. As was done with Ms. H, the first step is to stop alcohol and, if possible, potentially hepatotoxic medications, and then remeasure the liver enzymes. Although aspects of the history can increase the likelihood of a specific diagnosis, the history is not sensitive or specific enough to make a diagnosis, and it is necessary to test somewhat broadly. If liver enzyme abnormalities persist after stopping alcohol and potentially hepatotoxic medications, the American Gastroenterological Association recommends beginning with a PT; serum albumin; CBC; hepatitis A, B, and C serologies; and iron studies (serum iron, total iron-binding capacity [TIBC], ferritin).
IgM and IgG anti-HAV are both negative. HBsAg and IgM anti-HBc are negative; IgG anti-HBc and anti-HBs are positive. Anti-HCV is negative. The transferrin saturation is 35%, and the serum ferritin is 190 ng/mL.
Have you crossed a diagnostic threshold for the leading hypothesis, NAFLD? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Alternative Diagnosis: Hereditary Hemochromatosis
Textbook Presentation
Most patients are asymptomatic, but a few have extrahepatic manifestations of iron overload. Some patients are identified by screening the family members of affected individuals.
Disease Highlights
A. An autosomal recessive disease causing deficiency of the iron regulatory hormone hepcidin, leading to increased intestinal iron absorption and accumulation in tissues
B. Iron deposition occurs throughout the reticuloendothelial system, leading to a broad range of potential manifestations.
1. Liver manifestations range from hepatomegaly to fibrosis to cirrhosis; hepatocellular carcinoma risk is increased only in patients with cirrhosis.
2. Any joint can be affected, but the second and third metacarpophalangeal joints are typical.
3. Cardiac infiltration leads to cardiomyopathy.
4. Other manifestations include secondary hypogonadism (pituitary infiltration), diabetes (pancreatic infiltration), and hypothyroidism (thyroid infiltration).
C. There are several possible gene mutations; the most common is the HFE C282Y mutation, thought to have initially occurred in a Viking or Celtic ancestor.
1. In a meta-analysis of people of European ancestry with iron overload, 81% were homozygous for the HFE C282Y mutation.
2. 5% were compound heterozygous for the C282Y/H63D mutation.
3. In another study, nearly 100,000 primary care patients were screened for iron overload and HFE mutations; 299 homozygotes were found.
a. The prevalence of homozygosity was 0.44% in whites, 0.11% in Native Americans, 0.027% in Hispanics, 0.014% in blacks, 0.012% in Pacific Islanders, and 0.000039% in Asians.
b. The prevalence of heterozygosity for the mutation was 10% in whites, 5.7% in Native Americans, 2.9% in Hispanics, 2.3% in blacks, 2% in Pacific Islanders, and 0.12% in Asians.
D. The gene expression is quite variable, with the penetrance of iron overload in homozygotes (abnormal transferrin saturation or ferritin) ranging from 38% to 76%; clinical disease is found in only 2–38% of men and 1–10% of women.
E. 72% of patients with serum ferritin levels > 1000 mcg/L have cirrhosis, compared with 7.4% of those with ferritin levels < 1000 mcg/L.
F. Screening primary care populations for hemochromatosis is not recommended by the US Preventive Services Task Force or the American College of Physicians.
Evidence-Based Diagnosis
A. Liver biopsy with measurement of hepatic iron index is the gold standard.
B. Initial testing should be done with a transferrin saturation (serum iron/TIBC) and a serum ferritin (the test characteristics are for identifying homozygous patients).
1. Transferrin saturation ≥ 50% in men
a. Sensitivity, 82.4%; specificity, 92.5%
b. LR+, 10.9; LR−, 0.19
2. Transferrin saturation ≥ 45% in women
a. Sensitivity, 73.8%; specificity, 93.1%
b. LR+, 10.8; LR−, 0.28
3. Ferritin ≥ 200 ng/mL in men
a. Sensitivity, 78%; specificity, 76%
b. LR+, 3.25; LR−, 0.23
4. Ferritin ≥ 200 ng/mL in women
a. Sensitivity, 54%; specificity, 95%
c. LR+, 11; LR−, 0.48
C. Patients who have a transferrin saturation ≥ 45% and an elevated ferritin should undergo HFE gene testing, looking for the hereditary hemochromatosis mutations.
All first-degree relatives of patients with hereditary hemochromatosis should undergo gene testing, regardless of the results of the iron studies.
1. If C282Y/C282Y homozygous mutation is found
a. If age is < 40 years, ferritin < 1000 ng/mL, and transaminases are normal, proceed to treatment.
b. Otherwise, perform liver biopsy to determine severity.
2. If other mutations or no mutations are found, look for other causes of iron overload or perform liver biopsy for diagnosis.
Treatment
Periodic phlebotomy to reduce the iron overload has been shown to reduce the risk of progression to cirrhosis.
Alternative Diagnosis: Autoimmune Hepatitis
Textbook Presentation
The clinical presentation is variable, ranging from asymptomatic transaminase elevation to nonspecific constitutional symptoms, to advanced liver disease.
Disease Highlights
A. A chronic inflammatory disease of the liver, although 25% of cases present as acute hepatitis
B. Annual incidence of 1.4 cases/100,000; 3–4 times more common in women than in men
C. Wide age distribution, occurring in infants and octogenarians
D. 27% 10-year survival in untreated patients
E. Drug-induced autoimmune hepatitis, reported with minocycline, nitrofurantoin, atorvastatin, and infliximab, has a more benign course than idiopathic autoimmune hepatitis.
Evidence-Based Diagnosis
A. Autoantibodies
1. Antinuclear antibodies (ANA): sensitivity, 32%; specificity, 76%; LR+, 1.3; LR–, 0.89
2. Anti-smooth muscle antibody (SMA): sensitivity, 16%; specificity, 96%; LR+, 4; LR–, 0.87
3. ANA and SMA: sensitivity, 43%; specificity, 99%; LR+, 43; LR–, 0.57
4. Diagnostic criteria have been developed (Table 26-7).
Table 26-7. Diagnostic criteria for autoimmune hepatitis.
a. For a diagnosis of probable autoimmune hepatitis (6 points): sensitivity, 88%; specificity, 97%; LR+, 29; LR–, 0.12
b. For a diagnosis of definite autoimmune hepatitis (≥ 7 points): sensitivity, 81%; specificity, 99%; LR+, 81; LR–, 0.19
Treatment
A. Treatment is indicated for all patients with evidence of active inflammation, either by transaminase elevation or histology.
B. Prednisone alone, or prednisone and azathioprine are used to induce remission; occurs in 85% of patients
C. Many patients require maintenance therapy, most commonly with azathioprine.
D. Other immunosuppressive agents are used in patients who do not respond to or cannot tolerate the first-line treatments.
E. Liver transplant is often successful in patients with cirrhosis and decompensated end-stage liver disease, although autoimmune hepatitis can recur in the transplanted liver.
CASE RESOLUTION
Ms. H’s transaminase levels remained elevated after abstaining from alcohol and discontinuing medications, making those etiologies unlikely. Her hepatitis A and C serologies are negative; her hepatitis B serologies are consistent with a previous infection and not chronic hepatitis B. Her transferrin saturation is normal, and the slightly elevated ferritin is not specific for any particular disease. You order an ANA, SMA, ceruloplasmin, and alpha-1-antitrypsin levels and phenotype, all of which are normal.
At this point, NAFLD is by far the most likely diagnosis. An ultrasound is not absolutely necessary, but it could confirm the presence of steatosis.
Ms. H has an ultrasound, which shows an enlarged liver with diffuse fatty infiltration. She begins to walk 20 minutes 4 times/week, and reduces her portion sizes. Her transaminases remain stable for the next several months. One year later, she has lost 20 pounds, and her transaminases have decreased to around 40.
REVIEW OF OTHER IMPORTANT DISEASES
Acetaminophen-Induced Hepatotoxicity
Textbook Presentation
Most patients experience nausea, vomiting, malaise, and abdominal pain. While single overdose ingestion usually is a result of a suicide attempt, up to half of cases occur accidentally.
Disease Highlights
A. Maximum recommended dose of acetaminophen is 4 g/day; some experts recommend < 2 g/day in patients with decompensated cirrhosis or continued alcohol ingestion.
B. In the United States, acetaminophen overdose was the leading cause for calls to Poison Control Centers and accounts for 42% of acute liver failure cases.
C. Unintentional overdose, 48%; intentional overdose, 44%; remaining cases are unknown
1. 38% ingested ≥ 2 acetaminophen preparations simultaneously
2. 63% used opioid-containing compounds
D. Hepatotoxic effect is due to production of N-acetyl-p-benzoquinone imine (NAPQI)
1. NAPQI can be rapidly conjugated by hepatic glutathione to nontoxic metabolites.
2. Once hepatic glutathione stores are depleted by 70–80%, NAPQI binds to hepatocytes causing cellular injury.
a. Chronic liver disease and chronic alcohol ingestion cause depletion of hepatic glutathione, making acetaminophen toxicity more likely in these patients.
E. Toxicity is acute; transaminases typically increase 24–36 hours after ingestion and peak at 72 hours.
F. Maximal liver injury peaks 3–5 days after ingestion; jaundice, coagulopathy, and encephalopathy can be present.
G. Concurrent lactic acidosis is a poor prognostic marker.
1. Early lactic acidosis due to inhibition of mitochondrial function by NAPQI
2. Late lactic acidosis due to tissue hypoxia and decreased lactate clearance from acute liver failure
H. Screening for possible coingested substances and other causes of hepatitis should be considered, particularly if the history is uncertain.
Evidence-Based Diagnosis
A. AST is often > ALT and can exceed 10,000 international units/L.
B. Precise time and amount of acetaminophen intake are critical for diagnosis and management; a 4-hour acetaminophen level, or as soon after as possible, should be obtained.
C. Time after ingestion and acetaminophen levels should be plotted on the Rumack-Matthew nomogram which is used to guide whether administration of N-acetylcysteine (NAC) should be considered (Figure 26–6).
Figure 26-6. Outcome nomogram with the original ‘200’ line and the lower ‘150’ line. Patients with acetaminophen levels above the lower ‘150’ line should be treated with NAC. Percentages represent the percent of patients with AST > 1000 at any time during their course. (Reproduced with permission from Rumack BH: Acetaminophen misconceptions, Hepatology. 2004 Jul;40(1):10–15.)
Treatment
A. Activated charcoal
1. Effective at limiting acetaminophen absorption when given within 4 hours of ingestion
2. Contraindicated in patients with an unsecured airway or gastrointestinal tract injury
B. NAC is established antidote; the key to effective treatment is administering before ALT elevation.
1. Hepatotoxicity is < 5–10% when NAC is administrated within 8 hours of overdose; delays beyond 10 hours increase risk to 20–30%.
2. Liver transplant can be life-saving in patients who progress to severe acute liver disease.
Isolated Alkaline Phosphatase Elevation
Figure 26-7 outlines the diagnostic approach to a patient with an isolated elevation of the alkaline phosphatase.
Figure 26-7. Diagnostic approach to elevated alkaline phosphatase.
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