8/15 (HUP): alcoholic hepatitis

Late post thanks to boards! A big thanks to Dr. Vandana Khungar for helping us through the case of a young man who presented with jaundice and abdominal pain with a bilirubin of 51 and was ultimately diagnosed with acute alcoholic hepatitis (for which he got a liver transplant).

Key features of alcoholic hepatitis

  1. Even though we often think of alcoholic hepatitis as ‘acute’, its actually more often a manifestation of chronic heavy alcohol intake (>80g/day for a decade or more).

Ever wonder how much alcohol is in a ‘standard’ drink? Take a look!

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Remember that alcoholic hepatitis (AH) can be superimposed on underlying cirrhosis/chronic liver disease.

  • Patients can present with fever, tender hepatomegaly and leukocytosis; it can sometimes be difficult to distinguish from other causes of acute hepatitis, as well as sepsis/infection
  • Some series have shown that >50% of patients have abdominal bruits; other stigmata of liver disease (ascites, encephalopathy) may be present either with or without underlying liver disease
  • The AST:ALT ratio will usually be >2:1: thought to be due to hepatic deficiency of pyridoxal 5′-phosphate in alcoholics (a cofactor for the enzymatic activity of ALT); so the ratio is really a failure of ALT to increase appropriately

Risk stratification for alcoholic hepatitis

There are several risk scores used for EtOH hepatitis:

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Lucey. NEJM 2009.

 

Maddrey’s discriminant function: estimates EtOH severity; a score >32 is considered severe.
Glasgow score: used to estimate likelihood of benefit from steroids. Rarely used in clinical practice
Lille score: helps decide whether to stop or continue steroids after 1 week (ie which patients won’t benefit from steroids no matter what given the severity of their hepatitis)

How is alcoholic hepatitis managed?

  • Supportive care (fluids, antibiotics if needed, abstinence, nutritional support)
  • The big debate is over the role of prednisolone and pentoxifylline (a TNF-a inhibitor) in the treatment of alcoholic hepatitis. You can read the details of the STOPAH trial below (which compared the two), but the short answer is that it’s not totally clear that one is better than the other.
  • One major flaw of STOPAH may have been that in the groups randomized to steroids, the investigators continued prednisolone for 28 days instead of using the Lille score to stop steroids for those people that wouldn’t have benefited; in doing so, they may have driven up mortality due to infection in the steroid group and diminished any apparent benefit of prednisolone!
  • In clinical practice (at least at Penn), prednisolone is often started after 48 hours of negative infectious workup, as long as they don’t have renal failure (a population that was excluded in STOPAH, due at least in part to concerns about bleeding risk)

See reference #2 below for more information about the role of liver transplant in treating alcoholic hepatitis!

References

  1. Thursz M et al. Prednisolone or Pentoxifylline for Alcoholic Hepatitis (STOPAH). NEJM 2015.
  2. Saberi, B. et al. 2016. Current Management of Alcoholic Hepatitis and Future TherapiesJournal of Clinical and Translational Hepatology. 4, 2 (2016), 113–122.
  3. Lucey et al. 2009. Alcoholic Hepatitis. NEJM.

8/17 (HUP): diffuse GGOs and PCP

Thanks to Tom Franzon and Ben Manning for presenting two (different) patients who presented with subacute shortness of breath and were found to have diffuse groundglass opacities (GGOs) on chest CT and were ultimately diagnosed with HIV for the first time.

Along the way, we went through a diagnostic approach for diffuse ground glass opacities. Developing a differential for just ‘GGOs’ is a Herculean task, but creating a differential for diffuse GGOs (as opposed to scattered GGOs, particularly in association with some other consolidation) is actually much easier to do.

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Diffuse GGOs in a patient with methotrexate pneumonitis. AJR 2005.

Here’s a table from a paper by Penn radiologist/wizard Wally Miller:

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Miller and Shah, AJR 2005

This man was ultimately diagnosed with PCP pneumonia.

A few key points about diagnostic testing related to HIV and opportunistic infections:

  • Beta-D-glucan has excellent sensitivity (~95%) and specificity (~70-80%) for the diagnosis of PCP; in a patient who truly has PCP, BDG levels will likely be >400-500
  • CD4 counts can decrease with periods of acute/critical illness, so the CD4% may be a more stable marker to follow in someone with HIV, as it shouldn’t change all that much
    • An absolute CD4 count >500 corresponds to a CD4% of >30%

    • An absolute CD4 count between 200-500 corresponds to a CD4% of 15 to 30%

    • An absolute CD4 count <200 cells/microL corresponds to a CD4% of <15%

  • Most of the time, non-HIV related low CD4 counts don’t predispose to opportunistic infections, with the exception of idiopathic CD4+ lymphopenia— patients with this condition behave similarly to HIV+ patients with low CD4 counts in terms of OI susceptibility, except that they don’t have HIV!
  • Legionella urine antigen tests only for Legionella pneumophila serovar 1, so as a whole it has about a 70% sensitivity
  • The histoplasma urine antigen is best in HIV+ patients with disseminated disease (95% sens); sensitivity is probably similar in non-HIV patients
    • It’s really not a great test for less severe pulmonary histo or chronic cavitary histo, especially in non-AIDS patients
    • It can be false positive with other endemic fungi (Blasto, coccidio, etc)
  • A brief note on IRIS
    • It represents ‘unmasking’ of an underlying, unrecognized infection as the immune system ‘reconstitutes’ itself while on ART
    • Many pathogens (TB, NTBMB, PCP, HBV, crypto) have been associated with IRIS, while others (ex: toxo) are rarely associated with it
    • Generally develops when pre-ART CD4 nadir <100, and generally develop within one week to a few months after initiation of ART (depending on the kind of infection, host characteristics, etc)

References

  1. Miller, Wally Jr and Shah, Rosita. Isolated Diffuse Ground-Glass Opacity in Thoracic CT: Causes and Clinical Presentations. AJR 2005.
  2. Kauffman, C. Histoplasmosis: a clinical and laboratory update. 2007.
  3. Murdoch et al. Immune Reconstitution Inflammatory Syndrome (IRIS): review of common infectious manifestations and treatment options. 2007.

8/17 PPMC Report: AL-Amyloidosis

Today we discussed the case of a patient who presented with macroglossia and was found to have AL amyloid and multiple myeloma.

We reviewed physical exam findings to confirm macroglossia — including scalloped tongue and a thorough differential for macroglossia including amyloid, hypothyroidism, acromegaly, space occupying lesions (abscess v. hemangioma v. lymphangioma v. cyst etc.) and exceedingly rarely GCA (1).

Types of Amyloidosis:

Type of Amyloid Description
AL Deposits monoclonal light chains – associated with plasma cell dyscrasias but can occur alone!
AA Deposits amyloid A – associated with chronic inflammation (ie RA, IBD, spondyloarthropaties), frequently presents with nephrotic syndrome
Dialysis Related Deposits beta 2 microglobulin, has an osteoarticular prediliction
Hereditary/Familial Deposits transthyretin, alpha cahin of fibrinogen A, apolipoprotein
Age Related (Senile) Deposits transthyretin – clasicially cardiac presentation
Organ Specific 2/2 locally produced proteins rather than circulating

The PPMC Report Team did a thorough screen for other end-organ involvement including renal (nephrotic range proteinuria), hepatosplenomegaly, CHF/restrictive cardiomypoathy, peripheral neuropathy, and carpal tunnel syndrome. We also discussed the increased risk for bleeding diathesis in AL amyloid patients due to both liver involvement AND direct factor X deficiency due to factor X binding to amyloid fibrils.

PPMC Team identified the disease specific signs/symptoms of multiple myeloma…the CRAB!

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(hyperCalcemia >11, Renal dysfunction with Cr >2 , Anemia hgb <10, Bone disease >=1 lytic lesion)

We reviewed the different diagnostic criteria for plasma and lymphoplasmacytic cell dyscrasias (2):

PCD

We also reviewed the criteria for a patient with amyloidosis to qualify as having MM (3).  I may have misspoken during conference, so I just want to clarify here in this post: Patients with AL-amyloidosis who have >10% plasma cells on BMBx should be considered as having MM — Essentially pretend that smoldering myeloma doesn’t exist for AL-amyloid patients.

Our conference wrapped up with a discussion on cardiac amyloid and the medications in our arsenal to treat this disease: loop diuretics +/- spironolactone. Beta-blockers and CCB are contraindicated due to their negative inotropy and ACE-I are associated with significant hypotension (possibly unmasking some subclinical autonomic neuropathy). These patients should ALSO be considered for anticoagulation (with the help of a cardiologist) based on both rhythm and low atrial flow velocities.

 

References:

  1. Helfrich DJ, et al. Giant cell arteritis of the tongue presenting as macroglossia. J Rheumatol. 1988 Jun;15(6): 1026-8.
  2. American College of Physicians. MKSAP 17: Medical Knowledge Self-Assessment Program. Philadelphia: American College of Physicians,  2016.
  3. Kourelis TV et al. Coexcitent multiple myeloma or increased bone marrow plasma cells define equally high risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol. 2013 Dec;31(34):4319-24.

8/10 PPMC Report: Secondary Amenorrhea

Today we discussed the case of a 31 yo F with PMH of ?PCOS presenting with difficulty conceiving after attempting for 3 years.

First of all — the PPMC report team agreed that three years was too long! She should be referred for work up after 1 year (or 6 months if >35yo) of attempting to conceive (sex ~2x weekly) without resultant pregnancy.

We discussed the Rotterdam criteria to diagnose PCOS (2003).

Two out of three of the below:

  1. Oligo/anovulation
  2. Clinical/biochemical signs of hyperandrogenism
  3. Polycystic ovaries on US (>12 follicles)

WITHOUT other causes of hyperandrogenism present.

We reviewed the other causes of hyperandrogenism (…and when to go looking for them) including tumor (ovarian/adrenal), congenital adrenal hyperplasia, Cushing’s disease and acromegaly.

Amenorrhea

Following the above workup algorithm, our patient had hypogonadotropic hypogonadism and an MRI which demonstrated a pituitary mass. Given her presentation with hyperandrogenism, the PPMC report team went back and ordered a Cushing’s and Acromegaly work up which demonstrated elevated IGF-1 which did not suppress with a glucose load — diagnosing this patient with acromegaly 2/2 a hyperfunctioning pituitary adenoma!