12/14 PPMC Report: Wilson’s Disease

Today we discussed a really interesting case of Wilson’s disease. We all remember from medical school that Wilson’s disease is a problem with copper excretion:

Wilsons1.pngIn patient’s affected by this condition, the body’s normal mechanisms for excreting copper do not function appropriately, which leads to accumulation of free copper (and decreased ceruloplasmin), which then can get deposited in body tissues. The main sites that are affected are the liver, the cornea, and the brain. Neurologic manifestations of Wilson’s disease can include movement disorders, neuropsychiatric symptoms, and dysarthria. Corneal involvement is seen with presence of a Kayser-Fleischer ring. This disease can also be associated with a hemolytic anemia.

Degree of liver involvement can be variable, and in its most severe form can include acute liver failure. We reviewed criteria for acute liver failure:

Wilsons2

Of note, patients with Wilson’s disease and the top two criteria can still be considered acute liver failure even if there is underlying cirrhosis; this has important implications for status of transplant listing.

Wilson’s disease is suggested by low ceruloplasmin and elevated free copper in the blood. LFT abnormalities in a pattern of AST:ALT>2 and Alk Phos:T Bili <4 is also highly specific for this diagnosis.  In a less acute setting, copper chelators can be used for treatment. In acute liver failure, supportive measures can be helpful, and transplant is the definitive therapy. Plasmapheresis has also been reported in such cases!

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11/7 HUP Report – Acute Liver Failure due to HSV

Thanks to Dr. Khungar for joining our discussion about a very interesting case. Today we discussed a patient with a history of poorly-managed SLE who was hospitalized with concern for pleuritis/pericarditis and rapidly developed acute liver failure. In a matter of a couple days this patient’s liver function tests went from normal to peak values of AST >14000, ALT >6000, Alk Phos 144 and T. Bili 9.6.

We reviewed the clinical definition of acute liver failure:

ALF

Our patient met criteria for acute liver failure. Within the broad differential for this condition, there are not all that many pathologies that will cause transaminase elevation to the degree seen in our patient. Some things to think about include:

  • drug induced liver injury
  • acetaminophen overdose
  • ischemic liver injury
  • viral hepatitis (rarely)
  • HSV

Care for acute liver failure involves supportive measures and evaluating for liver transplantation. We also discussed some data suggesting benefit to administration of N-Acetylcysteine (NAC) even in patients who did not overdose on acetaminophen.

In a prospective, double-blind trial published in Gastroenterology, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.

Transplant free survival was significantly better in patients receiving NAC, with the most notable benefit in patients with coma grades I–II.

alf2

Our patient received an orthotopic liver transplant, and her explanted native liver stained positive for HSV. This is a rare cause of acute liver failure but should remain on your differential, particularly in patients at risk (including pregnant women or patients with compromised cellular immunity).

 

References:

Lee, WM et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. doi: 10.1053/j.gastro.2009.06.006. Epub 2009 Jun 12.

 

 

11/1 Presby report: pancreatic masses, with a helping of chronic diarrhea

Today we discussed the interesting case of a middle aged man with chronic diarrhea who was found to have a pancreatic mass, ultimately found to be a gastrinoma. We spent some time discussing pancreatic masses, as the differential doesn’t just start and end with pancreatic cancer!

Pancreatic masses are not a trivial problem: 2-20% of patients who get MRIs for other reasons will have a pancreatic cysts or other solid lesions!

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Mets to the pancreas are usually from RCC or melanoma, or occasionally ovarian cancer.

Pancreatic cysts vary in their malignant potential

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JAMA 2016

 


WORKUP OF CHRONIC DIARRHEA

There are 5 questions that will help you work-up chronic diarrhea:

  1. Is it really diarrhea? Make sure it’s not fecal incontinence due to chronic constipation or stool impaction/overflow
  2. Is it medication-induced? Beware of metformin, NSAIDs, PPIs, SSRIs, antibiotics, Mg-containing meds, mycophenolate mofetil; also sorbitol- or xylitol-containing gums, and herbal teas/supplements which contain sennosides or other compounds
  3. Is it factitious? (consider if stool osm <290 or >600, female healthcare worker age ~45)
  4. How long? acute (<2 weeks) vs chronic (>4 weeks) diarrhea
  5. What’s the diarrhea like? inflammatory (frequent/bloody BMs, fever) vs fatty (greasy, hard to flush, weight loss) vs watery diarrhea
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Mayo Clinic Proceedings 2012

The majority of people with chronic diarrhea do not need stool cultures! In patients with chronic diarrhea, the highest yield would be in immunosuppressed patients (AIDS, organ transplant, etc), as they are more likely to have prolonged infection with a pathogenic organism like Salmonella or Shigella; this type of prolonged infection just doesn’t happen in immunocompetent individuals.

Other pearls

  • CA 19-9 can be elevated in pancreatic cancer but ALSO in any cause of pancreatic inflammation; so it is very NONSPECIFIC, meaning you shouldn’t jump to order it on anyone with a pancreatic mass
  • Gastrinomas generally don’t require adjuvant chemo after resection since they’re so slow growing
  • Carcinoid tumors will only produce symptoms (flushing etc) once they’ve metastasized to the liver, even if they’re radiographically invisible by CT or MRI
  • Blastocystis hominis is a commonly seen fecal protozoan, but it’s not clear that it truly causes diarrhea; for most people, it’s probably just a bystander to some other cause of diarrhea
  • Fecal calprotectin is secreted by neutrophils, and is a sign of inflammation; it’s most commonly used in IBD, but any cause of inflammatory diarrhea would cause it to be elevated

A lot of this is pulled from Becca’s excellent post from the summer. Take a look at hers for more re: the workup of chronic diarrhea!

References

  1. AGA Guideline on Diagnosis/Management of Asymptomatic Neoplastic Pancreatic Cysts. 2015.
  2. Stark et al. Pancreatic cystic disease: a review. JAMA 2016.
  3. Sweester S. Evaluating the Patient with Diarrhea: A Case Based Approach. Mayo Clin Proc.June 2012;87(6):596-602.

10/23 Presby report: acute abdominal pain, terminal ileitis

Tim Day presented a great case of a young man with acute abdominal pain, and was ultimately diagnosed with epiploic appendagitis (NOT appendicitis). Along the way we waded into some of the murky waters surrounding diagnosis of acute appendicitis and reviewed some important physical exam maneuvers.

In patients in whom appendicitis is suspected, two historical features make it more likely:

  • migration of pain to RLQ (OR 3.4)
  • vomiting (OR 5.4)

The Alvarado score is a clinical decision rule that can help rule out a diagnosis of acute appendicitis.

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Higher scores predict a higher risk of appendicitis, while scores less than 4 indicate a low risk of appendicitis, such that imaging may be avoided.

Note: the Alvarado score is highly sensitive but not specific, so it’s good for ruling OUT appendicitis, but not ruling it in, particularly for the purpose of deciding on surgery. It also performs best in men, and may overpredict the probability of appendicitis in women.

A brief note on the antibiotics-first strategy: several European trials have attempted to give antibiotics first in an attempt to avoid surgery. While the data is heterogenous, generally the conclusions are that:

  • Antibiotic-first strategy can be considered in those who’ve had complications of prior intraabdominal surgery (fistulas, adhesions, etc)
  • The abx-first strategy is NOT associated with a higher risk of perforations or complications, but IS associated with a high risk of recurrent appendicitis

A quick note on the differential diagnosis of terminal ileitis: it’s not always Crohn’s!

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Bojic et al, 2011

One category to add to the list above: spondyloarthropathies (AS, reactive arthritis, psoriatic arthritis, etc).

References

  1. Bojic D et al. Terminal ileitis is not always Crohn’s Disease. Annals of Gastroenterology 2011.
  2. Flum D. Acute Appendicitis — Appendectomy or the “Antibiotics First” Strategy. NEJM 2015.

10/10 HUP Report – Small Bowel Mass

Today we discussed an interesting case of a patient with longstanding Crohn’s disease, well-managed off immunosuppression, who presented with an enterovesicular fistula. This is actually a really RARE complication of Crohn’s disease (approximately 3%), and almost always requires surgical intervention. Aside from being secondary to active inflammation from his IBD, this new clinical finding could be secondary to a small bowel neoplasm (small bowel cancer is also really rare, but the rate is increased in Crohn’s disease patients).

Here is our basic differential for a small bowel mass:

Malignant

  • Neuroendocrine tumor
  • Adenocarcinoma
  • Sarcoma
  • Lymphoma
  • Metastatic disease (hematogenous spread or direct spread from peritoneal carcinomatosis)

Benign

  • Lipoma
  • Fibroma
  • Leiomyoma
  • Adenoma
  • Desmoid tumor

Infectious

  • Tuberculosis
  • Abscess
  • Histoplasma

This patient’s biopsy was consistent with neuroendocrine tumor, and he had numerous metastases — this is a common finding at the time of diagnosis due to indolent and asymptomatic growth in many patients. First line treatment for neuroendocrine tumors is usually somatostatin receptor analogues. Symptomatic surgical debulking or curative surgical resection can be considered in appropriate candidates, but is less common. Prominent symptomatic liver mets can be managed with ablation techniques. Systemic chemotherapy can be attempted for refractory disease — everolimus, bevacizumab, and sunitinib have been used.

 

 

9/21 HUP Report: Evidence-Based Management of Severe Pancreatitis

Today we talked about management of severe pancreatitis and reviewed some of the evidence informing our practices.

First of all, how do we stratify severity of pancreatitis and why does it matter? It is really important to stratify severity because aggressive intervention for patients more likely to progress to severe pancreatitis can improve mortality.

Determining Severity

Revised Atlanta Criteria (for severity of acute pancreatitis):

  • Mild – no organ failure or systemic/local complications
  • Moderate – no or transient organ failure (<48 hrs) and/or local complications
  • Severe – organ failure >48 hrs, complications involving one or more organs

 

Lots of scoring systems have been devised, including Ranson’s Criteria, CT Severity Index, APACHE II, BISAP. They take into account variables like hemoconcentration (third-spacing in severe disease, studies with mixed findings based on cut-offs used), creatinine (possibly correlated with risk of necrosis), procalcitonin (most rapid acute phase reactant), CRP (most useful at 48 hours, >150 = severe), BUN (>20 at admission associated with increased risk of death). Some logistical considerations of the scoring systems:

  • BISAP is easy to clinically implement and comparable to APACHE II in predicting progression to severe disease
  • Ranson’s cannot be completed until 48 hours
  • APACHE II involves several clinical and lab data points that are not routinely obtained for all patients
  • CT Severity Index requires imaging, which is not always indicated

Overall, the American College of Gastroenterology recommends incorporating several clinical and laboratory parameters into an overall assessment of severity without relying on any particular scoring framework.

 

Fluid Resuscitation

Best results have been seen with aggressive fluid resuscitation in the first 12-24 hours. Lactated Ringers has been shown to be associated with lower incidence of SIRS at 24 hours than normal saline, with a theorized mechanism involving the development of metabolic acidosis with NS which potentiates activation of trypsinogen to trypsin (one of the active pancreatic enzymes causing autodigestion and inflammation).

 

Nutrition

Several studies support early enteral nutrition in severe pancreatitis, as compared with bowel rest and/or total parenteral nutrition. One theory suggests that bowel rest causes mucosal atrophy, which then may increase bowel translocation and risk of infection.

 

Prophylactic Antibiotics

Meta-analyses now suggest that there is no benefit to prophylactic antibiotics in this patient population. Antibiotics are only indicated if there is clinical concern for superinfection (which may be difficult to clinically differentiate from severe pancreatitis!). Antibiotics with good pancreatic penetration include carbapenems, high dose cephalosporins, metronidazole, and fluorquinolones.

 

 

Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013; 62:102.

Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 2013; 108:1400.

Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut 2008; 57:1698.

Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol 2011; 9:710.

Li J-Y, Yu T, Chen G-C, et al. Enteral Nutrition within 48 Hours of Admission Improves Clinical Outcomes of Acute Pancreatitis by Reducing Complications: A Meta-Analysis. Rakonczay Z, ed. PLoS ONE. 2013;8(6):e64926. doi:10.1371/journal.pone.0064926.

9/20 PPMC report: extra-intestinal manifestations of celiac disease

We discussed a young woman who presented with psychotic episodes and multiple micronutrient deficiencies, and was ultimately diagnosed with celiac disease.

Celiac disease is a systemic immune-mediated disease triggered by exposure to gluten (found in wheat, rye, barley) in genetically susceptible patients, who can then have a broad range of systemic manifestations and variable damage to the small intestinal mucosa.

PEARLS

  • It affects many races and ethnic groups (not just Caucasians)
  • There can be a variety of very subtle clinical manifestations
    • Chronic diarrhea, weight loss, abdominal distention (40-50%), recurrent abdominal pain
    • Iron deficiency (w/ or w/o anemia)
    • High transaminase levels, recurrent oral ulcers
    • Chronic fatigue
  • Untreated celiac disease can lead to neurologic disorders, infertility or recurrent abortion, and rarely cancer (T-cell lymphoma and adenocarcinoma of the jejunum)

Remember that celiac disease has a number of extra-intestinal manifestations

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NEJM 2016

Diagnosis: the IgA anti-tissue transglutaminase (TTG) antibody, which has excellent test characteristics (94% Se, 97% Sp). This is the single best initial test.

  • IgA anti-endomysial antibodies are nearly 100% specific, but should only be used to confirm a borderline +TTG (if there’s concern that it’s a false positive)
  • A small bowel biopsy is required to confirm the diagnosis if TTG+
  • If the diagnosis is uncertain, consider sending HLA DQ2/DQ8 testing; being negative for those haplotypes essentially rules out celiac (ie it has a very high NPV)

Remember: sensitivity of testing is markedly decreased when patients are on a gluten free diet, so don’t be too eager to restrict their diet! Biopsy findings on endoscopy can also be falsely negative if the patient is on immune suppression (steroids, etc).

A note on screening: no clear consensus exists on this, but consider screening 1st degree relatives of patients with celiac, and other high risk groups (unexplained IDA, Down syndrome, other autoimmune diseases w/ suggestive sx, etc)

In this case, the patient presented with psychosis at the age of 45, which is unusual: psychosis usually presents in the early 20s, and there’s also a small peak around menopause. While psychosis as a manifestation of celiac is rare, it’s important to remember the more (and more common) subtle neuropsychiatric signs of celiac.

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NEJM 2016

It’s very hard to avoid gluten- it’s present in tons of food (especially processed food) in subtle ways, and even in certain medications as a binder/filler; this makes adherence with a gluten free diet very difficult.

References

  1. Jackson J et al. Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatr Q. 2012.
  2. Kabbani et al. Celiac Disease or Non-Celiac Gluten Sensitivity? An Approach to Clinical Differential Diagnosis. Am J Gastroenterology 2014.
  3. Celiac disease. NEJM.