A Sinister Discoloration

This week in Morning Report, we discussed the case of two patients who presented to hospital with painless jaundice (i.e., hyperbilirubinemia). Initial workup revealed significant liver enzyme elevation, but in different patterns (hepatocellular vs. cholestatic). We went through an approach to liver enzymes, a broad differential diagnosis of liver injury, and a few ‘managerial’ pearls on inpatient vs. outpatient management of liver disease.

Let’s recap our learning from this case!

Scleral icterus. Image Courtesy of WikiMedia Commons.

1. To understand liver disease, you must understand a few key definitions, and the origin of a few key tests:

  • Hepatocellular liver disease: involves injury to hepatocytes (necrosis/apoptosis/destruction, often lymphocytic infiltration when seen on biopsy). This manifests as elevation in AST or ALT (see table below).
  • Cholestatic liver disease: involves impairment of bile flow, often due to narrowing or destruction of bile ducts. Biochemically, this is manifested as an elevation in ALP or GGT (or 5’NT – rarely used).
Approach to common liver chemistries. Note that these are liver enzymes, NOT liver function tests! The degree of elevation of the above does not correlate with liver synthetic function.

Remember that liver enzymes (transaminases) are different from liver synthetic function tests. The degree of transaminase elevation does not correlate directly with the degree of liver synthetic dysfunction. To understand the degree of liver synthetic dysfunction, remember the infamous ‘W’ from med school:

The ‘W’ of liver synthetic dysfunction. Caveats: May not always follow this order perfectly. Low platelets are often the earliest sign of liver dysfunction in the primary care setting. Hypoglycemia is a very late sign of liver failure.

2. As with anything, Diagnosis = Localization x Timecourse

Liver disease stems from pathology spanning a huge spectrum of disease from every subspecialty – autoimmune, infectious, inflammatory, neoplastic, drug-induced, etc.

I repeat this phrase often, but I really do mean it: Diagnosis = Localization x Timecourse. In liver disease, ‘Localization’ refers, broadly speaking, to hepatocellular vs. cholestatic disease. ‘Timecourse’ refers to acute vs. chronic onset of liver enzyme derangement. There are many ways to slice an approach to liver enzyme derangement, and I encourage you to explore different approaches. I really like this figure by Giannini et al. (CMAJ 2005) that summarizes the different temporal and demographic considerations when evaluating cholestatic or hepatocellular dysfunction.

Figure adapted from Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172(3):367-379. doi:10.1503/cmaj.1040752.

A few practical tips on working up liver enzymes derangement:

  • ConnectingON is your friend! It is imperative that you look through historical trends for both liver enzymes and liver synthetic function evaluation. Create a timeline for yourself, and try to answer the following questions if you can (this involves a bit of Sherlock Holmes-ing, which is what I love about hepatology):
    • When did liver enzymes start rising? In what pattern initially?
    • What were the synthetic parameters doing at that time?
    • Were there any new medications, illnesses, or events around that timeline that may have contributed to the derangement?
    • How long did the derangement last last? Did it wax/wane or steadily increase? Were any treatments initiated, and if so, what was the effect?

3. Have an approach to hepatocellular derangement (AST, ALT)

In general, I think of a few broad ‘buckets’ of AST/ALT derangement, summarized in the table below. I’ve also listed which tests to order and a few key diagnostic pearls, especially valuable for senior medicine trainees:

A detailed (but not entirely comprehensive) approach to hepatocellular liver enzyme derangement, along with a few high-yield exam and real-life clinical pearls

4. Have an approach to cholestatic liver enzyme derangement (ALP, GGT)

Similar to above, we also discussed an approach to cholestatic liver enzyme derangement, which I’ve summarized in the Table below, along with a few testing and clinical pearls:

A detailed (but not entirely comprehensive) approach to hepatocellular liver enzyme derangement, along with a few high-yield exam and real-life clinical pearls
Complications of liver disease. Image adapted from ‘Netter’s Illustrated Human Pathology’ by L.M. Buja and G.R.F. Krueger, 2nd Ed., Saunders Elsevier 2014.

5. A few ‘managerial’ pearls I’ve picked up over the years

  • Consulting: When in doubt, call a Hepatologist – I always learn so much from them when I pick up the phone to discuss a diagnosis!
  • Gold standard diagnosis: Don’t forget that a definitive diagnosis (drug-induced vs. autoimmune liver disease, for example) will likely require a liver biopsy
  • Transplant: Be aware of the possibility of liver transplant – this is a decision for Hepatology and Transplant Team, but all internists should be aware of the referral pathway
  • Inpatient vs. Outpatient management: This is a nuanced decision, and one I make in conjunction with my Hepatology colleagues. In general, if there is no evidence of synthetic liver failure (or if the synthetic failure is stable), if the patient is not encephalopathic, if they are able to manage nutritional intake adequately, and of course if they have no complications of decompensated cirrhosis (SBP, active variceal bleeding, etc.), they can likely be managed with close outpatient followup if there is ready access to a Liver Clinic where they can have close surveillance of liver enzymes, synthetic function, and access to specialist care.
  • Pre-Immunosuppression Management: We didn’t discuss it in detail, but if you are starting a patient on immunosuppression (e.g., prednisone) for autoimmune hepatitis, there is a host of pre-immunosuppression workup and screening to consider. For further details, refer to my other blog post here.

I hope you found this Morning Report useful – this is a large topic and we certainly didn’t cover everything. As always, please send your questions/comments to the CMR.

Note: These recaps are based on real-life cases presented during weekly Morning Report; however, no real patient findings/investigations/images/identifying details are used. Any clinical information presented has been modified and completely de-identified for privacy.

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