Last time we addressed symptomatic Acute Hepatitis. In contrast, “Chronic Hepatitis” usually refers to elevated liver function tests (LFTs), or more accurately transaminases — the ALT & AST — often discovered incidentally on a chemistry panel. What’s “elevated”? Probably >1.5- or 2-times-upper-limit of normal.
Repeat the LFTs again before embarking on a big work-up. The exception is for persons with risk factors for Hep B or C, since LFTs may fluctuate to & from normal in those cases. Main risks include:
- Hep B: Asian & African Immigrant; Children of Asian immigrant mothers; Injection Drug User (IDU); Men who have Sex with Men (MSM)
- Hep C: Transfusion before 1992; IDU; multiple sex partners
Review a medication history, especially for the most common med of all (alcohol). Statins and other meds may commonly increase the ALT a little (it’s nice to have obtained baseline LFTs first, so you won’t be confused). If a patient with high LFTs comes to you on the drug, stop it to retest, & then rechallenge and retest. Not that a 2-fold ALT rise is dangerous; you can still give your statin. But you want to have a diagnosis, & avoid more work-up.
By the way, don’t forget that the most important parameter for liver disease is “Synthetic Function.” We discussed Prothrombin Time with acute hepatitis; for chronic liver conditions, check the Protime and also the serum Albumin. Livers that can’t synthesize these 2 proteins are, virtually by definition, Cirrhotic.
- Caution re: the Albumin; it’s also a negative acute-phase reactant. Whereas the Sed Rate (ESR) and C-Reactive Protein go up with non-specific systemic inflammation, the Albumin may go down. So don’t necessarily blame a low albumin on hepatic failure.
The differential diagnosis of chronically increased transaminases is short [see Table]. A stepwise work-up tries to save money. If the Alkaline Phosphatase is disproportionately elevated, the differential is different [discussed later, below].
TABLE — Work-Up of Chronic Elevation of Liver Transaminases
|First Step Diagnoses
Tests to Order
Tests to Order
Hepatitis B — Diagnosed by a positive Hep B surface antigen (HBsAg). Repeat this in 6 months to be sure you didn’t happen to accidentally catch the tail end of an acute Hep B en route to clearing. Hep B virus clears spontaneously in 90% to 95% of people, who then remain immune forever. The rest wind up with chronic Hep B. [footnote: vertically-transmitted Hep B almost always becomes chronic].
WARNING: Chronic Hep B is complex. There are lots of variations & exceptions in its natural history & risks for cirrhosis & hepatocellular carcinoma. The following simplification is elegant (if I dare say so myself), but if not in the mood right now, scroll down to “Hepatitis C”.
For Chronic Hep B, the main test to order is the Viral Load: Hepatitis B Virus DNA (HBV DNA). Today, this is what defines “Chronic Active Hep B”.
- Be sure to order a “quantitative” viral load, to count viral copies. Not a “qualitative,” which only reports as “detected” or “not detected.” If the latter is cheaper, be sure the lab performs a “reflex to quantitative” count if the “qualitative” winds up being “detected.”
- HBV DNA is measured in both viral “copies” and “IUs” per ml.; one IU equals approximately 5 copies.
Hepatologists usually treat Chronic Hep B if HBV DNA >100,000 copies (20,000 IU). What’s considered a “high” viral load is very different for Hep B, Hep C, and HIV. One of my patients had a HBV DNA “>2.9 billion copies”!!! [how many virions can dance on the tip of a pin?].
Let Hepatology manage chronic Hep B unless you’re already used to doing it. But determine the “e-Antigen” status first:
- Hep B “e” antigen [HBeAg] — Positive suggests active disease, and also very infectious.
- Hep B “e” antibody [Anti-HBeAB] — Positive “e” antibody goes hand-in-hand with an absence of “e” antigen (this is a favorable case, good prognosis).
By the way, all the patients we’re discussing here, with a positive surface-antigen (HBsAg), are infectious to one degree or another. Vaccinate their sex partners & household members (Hep B is much more easily transmitted than Hep C and HIV). Then, from 1 to 6 months after their final vaccine dose, draw a HepB surface Antibody [anti-HBsAB] to prove the vaccine worked. This isn’t cost-effective for the general public, but is worth it for high risk contacts.
The tests we just discussed above, in a person with elevated LFTs and a persistently positive HBsAg, usually result in one of the following patterns:** “Chronic Active Hep B”:
- HBeAg positive, Anti-HBeAB negative
- HBV DNA usually a high-enough viral load to warrant treatment.
- This person is both very infectious, & personally at risk of eventual cirrhosis and/or hepatocellular carcinoma.
- HBeAg negative, Anti-HBeAB positive (i.e. immune system cleared e-antigen)
- HBV DNA is usually low or non-detectable.
- Need to follow the viral load over time.
- Will probably never get ill from HepB.
- Both HBeAg and the corresponding “e” Antibody are negative.
- This means a mutant virus infected the patient. Uncommon in the US.
- Very likely to cause sequelae of Chronic Active Hep B.
- Threshold for treatment is therefore a viral load of only 10,000 copies, or 2,000 IU.
Vertically-infected persons, usually from Asia, sub-Saharan Africa, or the Mediterranean, tolerate Hep B virus for many years. They don’t need treatment if their LFTs are normal; must wait until damage begins (usually in 20s or 30s).
Candidates for other organ transplants (not liver) or for major high-dose chemotherapy — a “HepB core IgG antibody” may be ordered, even if pts have normal LFTs and are negative for both HBsAg and Anti-HepB surface antibody. If positive, it’s called “Occult HepB,” implying that they had in fact been infected once, & a few virions may still be in them somewhere. They may warrant HBV DNA testing and often empiric Tx to prevent reactivation during the upcoming highly-immunocompromising procedure.
Chronic Carriers with very low or even undetectable HBV DNA, HBeAg Neg and thus converted to “e-Antibody” Positive, usually have normal LFTs. If theirs are significantly increased, maybe it’s due to another type of Hepatitis [!!!].
Confusing? Maybe it’s supposed to be.
Hepatitis C — Hep C is diagnosed by a positive Hepatitis C antibody. That’s easy. The next step is determining whether the infection is chronic. In contrast to Hep B, which is spontaneously cleared in 90% to 95% of persons, Hep C virus (HCV) persists in 80% to 85%. But there are still what we call the “Lucky 15,” those 15% of people who escape chronic disease.
Find the “Lucky 15” by ordering a Viral Load (HCV RNA by PCR). If it’s “undetectable,” the person is either virus free, or the initial positive Hep C antibody was false-positive. Repeating the antibody by a recombinant immunoblot assay (RIBA) will also distinguish, but don’t bother. If the viral load is undetectable, one way or another, there’s no chronic Hep C.
- So, if a patient has elevated LFTs, their Hep C antibody is positive, BUT their HCV RNA is undetectable, the LFTs are due to something else!!!
Order the Hep C viral load “qualitative, with reflex to quantitative.” The cut-off for qualitative (simply “detected” or “undetected”) is lower than for quantitative. So if you only order a quantitative, you might miss some (very few) cases of chronic infection with low viral loads. Those people still carry some risk of eventual liver damage. But for a “detectable” viral load, you certainly want to know how high. Also order a Genotype.
A high viral load isn’t prognostic; it only gives an idea as to likelihood of treatment success. A V.L. > 1-3 million is worse than if <1,000,000. Genotypes 2 & 3 are much easier to treat than 1 & 4, but disease progression is the same. The issue is of some concern because current Tx regimens often involve months of side effects.
Only a liver biopsy can determine how far the disease has progressed (proxy lab tests aren’t as accurate as we’d like). The most common system stages “Fibrosis” from 1 to 4. Stage 4 Fibrosis = Cirrhosis. Hepatology, who usually does the biopsy, will explain results to patients, but it’s good for you in primary care [or wherever] to have some insight.
- Definitely urge treatment for Stage 3 Fibrosis, before it becomes Stage 4
- Stage 4 Fibrosis responds poorly; transplant in the wings
- Stage 1 is so mild, treatment can definitely wait. Repeat biopsy in 4-5 years to get a sense of how rapidly Hep C is progressing in that given patient.
- Stage 2 is tricky. It responds better to Tx than Stage 3. But with a patient for whom you can date infection to 30-40 years ago (e.g. Hx blood transfusion, or IDU that’s been clean since then), a Stage 2 seems pretty reassuringly non-progressive.
- If HIV-coinfected, likelihood of progression is so high that Tx warranted no matter what, so biopsy may not be needed
Biopsy also reports Grades of “Inflammation” from 1 to 4. Higher Grades suggest increased likelihood of future progression, but Not Useful in terms of treatment response. For example:
- Stage 1 Fibrosis, Grade 4 Inflammation means the disease hasn’t progressed at all, but may in the future.
- Stage 3 Fibrosis, Grade 1 Inflammation may mean things aren’t progressing currently, but have certainly advanced a lot since initial infection (warrants Tx).
Hemochromatosis — Not an uncommon cause of asymptomatic elevated LFTs, depending on ethnicity. It’s an important diagnosis, because the disease is treatable, and cirrhosis inevitable if missed. Diagnose by finding a transferrin saturation >60%. Then confirm with biopsy.
The “Trans Sat. Pecent” is calculated from a serum iron and “total iron binding capacity,” & should be reported whenever an iron & TIBC are ordered. Don’t order a serum “transferrin,” which will measure the amount of that protein. You want the “transferrin saturation percent.” Order serum iron & TIBC.
Ultrasound — Well, this isn’t a disease, but include it in your work-up, primarily to find metastases from an occult cancer. It’ll also identify biliary tract abnormalities, and the new and common diagnosis “non-alcoholic steatohepatitis” aka “NASH.” Actually, not. Many other chronic liver diseases reveal fatty liver on ultrasound. And NASH, after all, is untreatable.
Second Step Testing (if no diagnosis made with above tests)
Thyroid Disorders — Either hyper- or hypothyroidism can elevate the LFTs. Order a TSH as a screen. Order it sooner if other signs or symptoms are suggestive.
Wilson’s Disease — A rare cause of elevated LFTs, virtually always presenting <40 years old, usually <30. I’ve never seen a case, but always seek it, because it’s 100% treatable & 100% fatal otherwise. A serum ceruloplasmin, if abnormally low, identifies >85% of cases. For a younger person with persistently high LFTs and no diagnosis, a 24-hour urine for copper finds the others.
You can also look for the 100% specific (but not very sensitive) Kayser-Fleischer ring: brownish discoloration of the superior edge of the cornea. It’s most easily found by slit lamp.
Celiac Disease — Rarely will celiac disease present with elevated LFTs alone. The best serum tests are the tissue transglutaminase (tTG) antibody and endomysial antibody, IgA fractions. Order these sooner in your work-up if you get a history of chronic GI symptoms, especially diarrhea.
Muscle Disorders — The AST & ALT are also muscle enzymes. Elevation might be due to strenuous exercise, recent injury or seizure, chronic muscle disorders. The serum creatinine kinase (CK, aka CPK) should be equally elevated.
Autoimmune Hepatitis — Screen with a serum protein electrophoresis (SPEP), looking for a polyclonal elevation of gamma globulins. If found, order an ANA and smooth muscle antibody, which aren’t very sensitive. Biopsy may be necessary for diagnosis.
- Note that a “smooth muscle antibody” is NOT the same as an “anti-Sm,” which stands for “Smith” & is found in Lupus. You have to completely write out “anti-smooth muscle,” & then be sure your lab doesn’t request the wrong test from their reference lab.
Anorexia Nervosa — Studies describe increased LFTs in young women with known anorexia nervosa; there’s no report of occult A.N. picked up incidentally. Still, you might inquire about eating habits as part of your work-up.
α-1 Antitrypsin Deficiency — This usually presents in early childhood. Certainly consider it in a COPD patient who never smoked, or if COPD occurred at a young age. A low level of α-1 antitrypsin is diagnostic; an absence of α-1 antitrypsin spike on SPEP may be a clue. However, any chronic inflammation may raise α-1 antitrypsin levels enough to generate false negatives.
Diagnostic biopsy for chronic transaminase elevation rarely finds anything except fatty liver. It’s necessary prior to invasive treatment of hemochromatosis or Wilson’s disease, helps confirm autoimmune hepatitis (though histology may not be specific), & diagnoses the extremely rare heredity bile ductopenia. More & more, hepatologists are refraining from routine diagnostic biopsy (as opposed to staging biopsy for chronic Hep C). If LFTs are persistently >3 times upper limit of normal, biopsy is hard to avoid.
Biopsy certainly confirms and stages “NASH,” the inevitable diagnosis for lot of patients with elevated LFTs and completely negative work-ups. Most patients with NASH will never have sequelae. Still, some progress to cirrhosis in their 40s and 50s. It’s impossible to identify who, & no treatment exists except transplant.
Beware the phrase “fatty liver.” Controlling serum lipids is irrelevant. Losing weight, if obese, may prevent progression, but there are people with severe NASH who don’t meet society’s view of “fat”.
ELEVATION OF ALKALINE PHOSPHATASE
When transaminases are normal or minimally elevated, & the Alk. Phos. high, the differential is small.
First Step: Determine what’s producing the alkaline phosphatase: liver, bone, intestine, or placenta. The last occurs in the 2nd or 3rd trimester and shouldn’t be too hard to identify. Rule out high intestinal Alk. Phos. via a fasting specimen (the enzyme rises post-prandially).
Distinguishing Liver from Bone fractions is best done by ordering a 5´-nucleotidase [pronounced “5-prime”] or a gamma glutamyl transpeptidase (GGT). If either is elevated to the same extent as the Alk. Phos., you’re dealing with liver disease. If they’re normal, wonder about bone disorders.
Don’t order “Alk. Phos. Isoenzymes.” The technology isn’t reliable in commercial labs.
Second Step: If the 5´-nucleotidase or GGT have confirmed the elevated Alk Phos comes from the liver, order:
- an Abdominal (or RUQ) Ultrasound to R/O biliary tract obstruction
- an anti-mitochondrial antibody (AMA) to diagnose primary biliary cirrhosis (PBC)
- an RPR or VDRL for 2° Syphilis
If ultrasound reveals dilated bile ducts, you’re home — send the patient on to GI for endoscopic retrograde cholangiopancreatography (ERCP), to diagnose obstruction due to masses, stones, or even primary sclerosing cholangitis.
If ultrasound shows normal ducts but abnormal liver parenchyma, order the same work-up as for elevated transaminases. If that’s unrevealing, a biopsy is probably in the wings.
If the AMA is high, you’ve pretty much diagnosed PBC. It’s debatable if a liver biopsy is necessary for confirmation, or if primary care can start treatment on your own. Certainly treat 2° Syphilis if the RPR is pretty high and confirmatory test positive.
If everything’s normal, & you’re sure this is liver & not bone, you’re stuck. Wing it: if the Alk. Phos. is <50% elevated, just keep watching. If higher, bail out to GI for a possible biopsy.
And what if both Alk. Phos & transaminases are elevated? You could be dealing with either hepatocellular disease or obstruction. Start your work-up with whichever seems predominant, but resign yourself to searching for all possibilities.
C’est ça [pronounced “SAY — SA” = “that’s that” (in French)]! Hope all this was helpful.
Thank you! Very interesting. I will definitely keep checking back for more posts in the future.
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