Topics in Hepatology

From 2010 Update in Gastroenterology and Hepatology for the Primary Care Practitioner

Christopher L. Bowlus, MD, Associate Professor of Medicine and Director, Gastrointestinal Fellowship Training Program, Division of Gastroenterology and Hepatology, Department of Internal Medicine,
University of California, Davis, Health System, Sacramento, CA

Educational Objectives

The goal of this program is to improve the management of the patient with abnormal liver tests, and the evaluation and treatment of patients with hepatitis B virus (HBV) infection. After hearing and assimilating this program, the cli­nician will be better able to:

1.   Employ liver tests to screen for specific liver diseases.

2.   Evaluate and diagnose the patient with chronic mildly elevated alanine transaminase (ALT) levels.

3.   Identify and screen patients at risk for hepatitis B virus (HBV) infection.

4.   Evaluate the HB surface antigen (HBsAg)-positive patient and classify his or her stage of HBV infection.

5.   Prescribe a recommended first-line therapy for the treatment of chronic HBV infection.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Bowlus has received hon­oraria from Bristol-Myers Squibb and Gilead Sciences. The planning committee reported nothing to disclose.

Abnormal Liver Tests

Role of liver tests: monitor for hepatotoxicity; screen for liver disease (LD); assess liver function; diagnose specific LDs

Assessment of liver function: difficult; liver has multiple functions but no clinically valid ways to measure them other than bilirubin and albumin; excretion  —  measured by bilirubin; not abnormal until later in LD; poor excretion can also be due to obstruction in otherwise normally functioning liver; synthesis  —measured by international nor­malized ratio (INR), albumin, and cholesterol; each can be influenced by multiple factors; metabolism and transport  —  no clinically available tests

Assessment of liver structure: during early stages of LD, focus more on assessing structure; liver imaging  —  ultrasonography (US); computed tomography (CT); magnetic resonance imaging (MRI); imaging largely nonspe­cific and does not allow good assessment of structure; liver biopsy  —  gold standard for showing liver structure; used primarily to stage disease; also used to grade inflammation and (rarely) to establish diagnosis; caveats  —  problems with sampling error; amount of tissue and location of sample strongly influence accuracy of staging; dif­ferences in interpretation by same or different pathologist

Prognosis: once LD progresses beyond early stages of fibrosis to cirrhosis, assessment focuses on prognosis; model of end-stage LD (MELD) score used to calculate patient’s chance of survival; slightly easier to calculate than Child-Pugh score (requires only creatinine, bilirubin, and INR); accurately predicts short-term survival; used to de­termine priority for liver transplantation

Serum liver tests: hepatocellular enzymes  —  aspartate transaminase (AST); alanine transaminase (ALT; more liver specific); biliary enzymes  —  alkaline phosphatase (ALP; also found in other tissues); g-glutamyltransferase (GGT) helps confirm that elevated ALP of liver origin; isolated elevation of GGT of no concern

Patterns of liver injury: hepatocellular  —  mild ALT elevation (<200 IU/L; injury usually chronic; patient asymp­tomatic); severe ALT elevation (>200 IU/L; injury usually acute and symptomatic); cholestatic  —  primarily ele­vated ALP; sometimes elevated bilirubin

Patient evaluation: history  —  establish amount of alcohol use; exposure to viral hepatitides (eg, sexual activity, in­travenous [IV] drug use; transfusions before 1990); drug use (illicit; herbal remedies; supplements; prescribed medications); diabetes; immigration from areas with high prevalence of hepatitis B (HB); physical examination (PE)  —  look for signs of chronic advanced LD (spider angiomas; palmar erythema; temporal wasting; hepatomeg­aly; splenomegaly)

Evaluation of mildly elevated ALT: some controversy over what constitutes abnormal ALT level; 2002 study by Prati et al found cutoff for normal <30 IU/L in men, <19 IU/L in women (much lower than cutoff levels typically used in reference laboratories); study by Kim et al showed strong correlation between serum ALT level and risk for liver-related mortality; large overlap between clinically insignificant and clinically significant ALT elevation makes it difficult to classify patients

Differential diagnosis for patient with chronic mild ALT elevation: fatty LD (FLD; nonalcoholic FLD or steato­hepatitis [NAFLD, NASH]); alcoholic hepatitis; hepatitis C (HC); HB; drugs or toxins; hemochromatosis; auto­immune hepatitis (AIH); a₁-antitrypsin deficiency (AATD); Wilson disease; cryptogenic LD

Alcoholic LD: characterized by more than 2 to 4 drinks/day; AST/ALT ratio >2; AST or ALT <300 IU/L (if >300 IU/L, look for cause in addition to alcohol)

Disease-specific tests: viruses  —  HB surface antigen (HBsAg), HC virus antibody (HCV Ab); hemochromatosis  —  transferrin saturation; AIH  —  antinuclear antibody (ANA); Wilson disease  —ceruloplasmin; AATD  —  serum AAT level; caveats  —  ANA positive in many patients but usually present in low titers (higher titers indicate AIH); pa­tients with chronic LD (eg, viral hepatitis or FLD) often have high serum iron indices and elevated transferrin satu­ration; important to differentiate primary iron overload (hemochromatosis) from secondary (HC; alcoholic LD; NASH); HFE genotype screening helpful in ruling out hemochromatosis

Indications for testing patient with ALT >1.5 times upper limit of normal (ULN): if symptomatic, elevation of 6-mo duration, or risk factors for HBV or HCV, do immediate investigation; otherwise, have patient discontinue alco­hol and/or medications and  retest ALT; if still elevated, start investigation; evaluation should initially include Hb­sAg and  HCV Ab; if negative, do transferrin saturation, ANA, ceruloplasmin, AAT level, and get US; if all tests negative and US shows fatty liver, diagnosis of FLD strongly suggested

Take-home message: much overlap of clinically significant ALT with “normal” values; mild elevation of ALT re­quires thorough investigation

Severe acute hepatocellular pattern of injury: patients typically symptomatic; if signs of liver failure (eg, encepha­lopathy, coagulopathy), refer to transplant center; differential diagnosis  —  viral hepatitis; medications and toxins (particularly supplements); ischemia; AIH; Wilson disease

Cholestatic pattern of injury: differential diagnosis  —bile duct obstruction; primary biliary cirrhosis or sclerosing cholangitis; medications or toxins; total parenteral nutrition (TPN) therapy; infiltrative disease, eg, sarcoidosis 

Isolated hyperbilirubinemia: unconjugated bilirubin enters hepatocyte, conjugated, and excreted into biliary sys­tem; location of problem determines whether patient has elevated indirect or direct bilirubin; isolated elevated bili­rubin with normal ALP often due to hemolysis, shunts, and/or Gilbert syndrome; all examples of indirect hyperbilirubinemia (bilirubin level typically 6 mg/dL)

Outcome if abnormal liver tests not worked up further in primary care: not much data; results of study of hospi­talized patients with abnormal GGT, ALP, or ALT suggest that if abnormal liver tests not worked up, physician will miss serious LD in »10% of cases; thus, even patients with mildly elevated ALT require full investigation

Concluding comments: ALT far from perfect test and does not reflect severity of LD; liver structure used to assess severity of disease; most LDs can be diagnosed without liver biopsy (but requires thorough investigation)

Differentiating diabetic from nondiabetic patient when working up abnormal ALP (Question): FLD higher in diabetic population but also seen in nondiabetics (particularly those with insulin resistance [IR]); patient of most concern nondiabetic who is not obese; use homeostatic model assessment (HOMA) to calculate IR; if no IR, must be careful in labeling patient with FLD who could have other form of LD; if patient diabetic, all tests negative and US shows or suggests FLD, speaker does not investigate further

Hepatitis B Virus (HBV)

Introductory remarks: HB major problem (350 million people infected with HBV worldwide); physicians in pri­mary care practice need to screen adequately for HB and consider starting and maintaining treatment in appropriate patients (medications currently used have very low side effect profiles and can easily be managed in primary care setting)

HBV infections: acute  —  typically short term (<6 mo); often asymptomatic; occasionally causes liver failure; chronic  —completely asymptomatic; characterized by presence of HBsAg for >6 mo; infection can progress from acute to chronic

Transmission of HBV: varies depending on type of infection; vertical (mother to infant) transmission typical in areas of endemic infection; behavioral risk factors  —  unprotected sex; IV drug use; tattoos; needle sharing

Outcome determined by age at time of HBV infection: if during perinatal period, 0% risk for symptomatic disease, »90% risk for chronic infection; if acquired in adolescence or young adulthood, 40% risk of becoming symptom­atic, 5% to 10% risk for chronic infection

Prevalence of HBV worldwide: low  —  North America; parts of South America; Western Europe; intermediate  —  Eastern Europe; North Africa; high  —  >8% of population carries HbsAg; Asia; sub-Saharan Africa; native Alaskan population; in most of world, >2% of population HBsAg carriers

Prevalence of HBsAg in United States: <1% in non-Asian US population; »2% in US-born Asian-Pacific Islander (API) college students; »3% in API-born students; much higher in Chinese, Korean, and Vietnamese populations

Centers for Disease Control and Prevention (CDC) recommendations for HBV screening: persons born in areas with HBsAg prevalence ³2%; US-born persons not vaccinated as infants, with parents born in areas with HBsAg prevalence ³8%; all pregnant women; infants of HBsAg-positive women; populations with other risk factors

Take home message: screen all persons at risk for HBV; screen and immunize family members and household con­tacts of those found to be of HBsAg-positive

HBV viral and serologic markers: HBsAg  —  presence of infection; HBV DNA  —  viral replication (HB E-antigen [HBeAg] previously used as marker, but now know patients without HBeAg can still have active viral replication); HB surface antibody (anti-HBs)  —  immunity present (typically after vaccination); HB core antibody (anti-HBc)  —  exposure (but does not indicate active infection); HBeAg  —  active infection; HB E-antibody (anti-HBe)  —  inactive virus (seroconversion)

Natural history of HBV infection: immune tolerance stage  —occurs after acute infection of hepatocytes; virus very active and  prolific, but not yet recognized as foreign by immune system; can last weeks to years; HBV DNA ele­vated, HBeAg positive, ALT normal; if done, liver biopsy appears normal; immune clearance stage  —  immune-sys­tem recognizes HBV as foreign invader and begins to clear infected hepatocytes and mount inflammatory response; active hepatitis develops; ALT rises (key change), HBV DNA still elevated, HBeAg still positive; inactive carrier stage  —  viral replication ceases; HbeAg and  HBV DNA become negative, ALT normalizes, inflammation sub­sides, but patient retains HBsAg; small percentage of patients go on to develop immunity (ie, lose HBsAg; rarely happens with chronic infection); reactivation stage  —  inactive carriers can also become reactivated (HBeAg nega­tive; HBV DNA and ALT elevated; biopsy shows active disease); patient evaluation  —  must know HbeAg status, viral load (HBV DNA) and ALT to determine stage of infection

Typical course of HBeAg-negative HB (reactivation stage): characterized by recurrent flares of elevated ALT and HBV DNA, that drop back down to normal; can be difficult to distinguish, because at times, looks like inactive car­rier; physician must follow patients over time (eg, 6 mo) to detect active flares of disease

Outcome from HB: lifetime risk for death from hepatocellular cancer (HCC) or cirrhosis »25%; unlike HC, which progresses to cirrhosis, then to HCC, »30% of patients with chronic HB progress directly to HCC; patients who de­velop cirrhosis have »2% annual risk of developing HCC

Summary: chronic HB defined by presence of HBsAg; can be HBeAg positive or negative; evaluation of HBsAg-positive patient should include HBeAg, anti-HBe, viral load, and ALT (based on these, can classify stage of HB in­fection, and if followed over time, whether patient has  HBeAg-negative hepatitis)

HCC in chronic HB: risk factors  —  male sex; age >45 yr; family history of HCC; high viral load or active disease; screening for HCC  —  some disagreement over screening standards for patients with noncirrhotic HB (some screen all patients; speaker delays until patient >40 yr of age, unless family history present); typically done with US and a-fetoprotein (AFP) every 6 mo; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV (REVEAL-HBV)  —  13-yr study from China of patients with untreated HB showed screening effective in re­ducing deaths due to HCC; study demonstrated that baseline viral load correlates directly with risk for HCC, and for cirrhosis

Treatment options for chronic HB: entecavir; tenofovir; peginterferon a-2a (first-line therapies); adefovir, lamivu­dine, and telbivudine not first-line due to risk for viral resistance; single-agent therapy associated with very low rate of resistance

Summary: screen patients at risk (HBsAg); large evidence that vaccination for HBV decreases risk for HCC; evalu­ate HBsAg positive patients; screen appropriate patients for HCC; treat HBsAg-positive patients who require ther­apy

Questions and answers

Should native African patient with HBV be screened earlier for HCC? physician should consider screening Af­rica-born (and African-American) patients earlier; speaker tends to be less aggressive but would definitely start by 40 yr of age; moderator  —  for medicolegal reasons, recommended that screening of African patient with HB begin at 20 yr of age

Hepatitis D (HD): viral infection frequently seen in patients with history of IV drug use; inactive by itself; requires HB replication to cause disease (patients who are coinfected tend to have more advanced disease); some physicians routinely screen for HD; speaker does not, unless patient has flare of disease suggesting its presence

How often and how long should patient with negative viral load be tested? during first year, recommends testing ALT every 3 mo, HBV DNA every 6 mo; unclear whether necessary to continue testing if patient still not showing viral activity after 1 to 2 yr

Important point: patients with HB placed on immunosuppression or chemotherapy, they must be treated, even if dis­ease inactive

Role of anti-HBc in determining necessity of vaccinations: as mentioned, can get anti-HBs to determine if patient has developed immunity, can also get anti-HBc test; if patient anti-HBc-positive, anti-HBs-negative, likely still im­mune; could still vaccinate, but unclear if necessary

Acknowledgements

Dr. Bowlus lectured at 2010 Update in Gastroenterology and Hepatology for the Primary Care Practitioner, held August 28-29, 2010, in Monterey, CA, and sponsored by the University of California, Davis, Health System. The Audio-Digest Foundation thanks Dr. Bowlus and the UC Davis Health System for their cooperation in the production of this program.

Suggested Reading

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