1/18 PPMC Report: Hypoglycemia

Today we discussed a case of a 40 y/o M with no significant PMH who had spells of confusion, diaphoresis, blurry vision and paresthesias and was ultimately found to be profoundly hypoglycemic.

We reviewed the basic ways in which the healthy body manages glucose homeostasis:


Keeping it simple, if there is an increase in circulating glucose, the pancreas senses this and its beta cells secrete insulin, which has the following effects:

  • stimulates the liver and skeletal muscle to store glucose as glycogen
  • stimulates tissue cells to take up glucose
  • inhibits gluconeogenesis and ketogenesis in the liver

These actions reduce circulating glucose levels, store glucose for later use, and inhibit use of alternative metabolic fuels when glucose is present.

Conversely, when there is a decrease in circulating glucose, the alpha cells of the pancreas secrete glucagon, which has the following effects:

  • stimulates glycogenolysis, or breakdown of glycogen into glucose
  • stimulates gluconeogenesis, or production of glucose (in the liver)
  • stimulates ketogenesis, or production of ketones (in the liver)

Together these actions mobilize stored glucose, create new glucose, and then create ketones to be used as an alternative metabolic fuel when glucose is scarce.

Pathologic hypoglycemia should be suspected in the presence of Whipple’s Triad:

  1. Symptoms consistent with hypoglycemia
  2. Low plasma glucose while symptomatic
  3. Relief of symptoms once glucose level is raised

Our basic differential for hypoglycemia includes the following:

  • Drug/toxin
    • Exogenous insulin
    • Insulin secretagogues (ex: sulfonylureas – not insulin-sensitizing agents!)
    • EtOH
      • Inhibits gluconeogenesis but not glycogenolysis, so EtOH only causes hypoglycemia after long periods of drinking without oral intake – after glycogen stores are depleted
    • Long list of other culprits (commonly in association with insulin or underlying hepatic/renal dysfunction)
  • Endogenous hyperinsulinism
    • Beta cell secretagogue
    • Beta cell tumor (insulinoma)
    • Functional beta cell disorder (hypertrophy and hyperfunction)
      • Nesidioblastosis
      • Post-gastric bypass hypoglycemia
    • Insulin autoimmune hypoglycemia
      • Antibodies to insulin receptor or to insulin (usually in patients on insulin)
      • Ab-insulin complex circulates and dissociates in an unregulated fashion, which can cause relative hyperinsulinemia and resulting hypoglycemia
      • Or antibody can stimulate insulin receptors and mimic downstream effects (similar to Grave’s disease and TSH-R stimulating Abs)
  • Other
    • Sepsis – cytokine-accelerated glucose utilization
    • CKD – unclear pathophysiology, probably related to increased insulin sensitivity (since insulin is renally-cleared) and inhibition of gluconeogenesis
    • Hepatic failure – impaired gluconeogenesis
    • Adrenal insufficiency – partly related to loss of cortisol-induced gluconeogenesis and epinephrine-induced hyperglycemia
    • Non-islet tumors – usually related to incompletely processed IGF2
    • Malnourishment
    • Critical illness

Workup is most informative when the patient is hypoglycemic! You can challenge a patient with a 72 hour fast if symptoms present during fasting, or a mixed-meal challenge if symptoms are post-prandial. Check these labs:

  • Insulin level: make sure to check which types of insulin are detected on your assay. Elevated insulin level in the setting of hypoglycemia is inappropriate.
  • Proinsulin and C-peptide level: Proinsulin is cleaved into active insulin and C-peptide, so these will both be elevated in cases of endogenous hyperinsulinemia.
  • Beta hydroxybutyrate: insulin is antiketogenic, so in cases of inappropriately elevated insulin, switching metabolic pathways is impaired and BOHB is not elevated
  • Glycemic response to glucagon: insulin is antiglycogenolytic,¬†so excess¬†insulin inhibits breakdown of¬†glycogen in the liver. Insulin-mediated hyperglycemia patients will thus be able to respond to glucagon (which promotes glycogenolysis) by releasing glucose since they still have glycogen stores. In a normal patient, by the end of a fast most¬†glycogen will be depleted so response is diminished.
  • Sulfonylurea screen and anti-insulin antibody test

During hypoglycemic episodes, the following lab patterns can be observed:

  1. Non-insulin dependent:
  • insulin –¬†low
  • c-peptide and proinsulin – low
  • BOHB – high
  • Glycemic response to glucagon – low

2. Exogenous insulin:

  • insulin – markedly elevated
  • c-peptide and proinsulin – low
  • BOHB – low
  • Glycemic response to glucagon – high

3. Endogenous insulin

  • insulin – high
  • c-peptide and proinsulin – high
  • BOHB – low
  • Glycemic response to glucagon – high
  • Check sulfonylurea screen and anti-insulin Abs if this pattern is detected

If labs are consistent with an endogenous insulin source, various imaging modalities are available to evaluate for insulinoma, which was the diagnosis for our patient. Surgical resection/enucleation is usually the best treatment option, but anatomy and other comorbidities can make this complicated in certain cases!






1/17 VA report: hypercalcemia and the milk-alkali syndrome

Thanks to Dr. Wahba for walking us through his approach to hypercalcemia.

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Images courtesy of Choksi P, UMichigan

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Ddx for hypercalcemia. Source: http://www.wchcmr.org


We also talked about the milk-alkali syndrome (MAS). It was first described in the early 1900s after (Doctor) Sippy (what a great name) came up with a calcium-laden milk and antacid regimen for the treatment of peptic ulcers. The introduction of PPIs and H2 blockers in the 1970s caused a dramatic decline in its incidence, but recent years have seen a resurgence due to the widespread use of Ca carbonate and Vit D supplementation for osteoporosis. It is now thought to be the 3rd most common cause of in-hospital hypercalcemia, after hyperparathyroidism (#1) and malignancy (#2)!

“Old” MAS: middle aged men with GERD taking Tums
“Modern” MAS: older women with osteoporosis, ESRD patients or those on chronic steroids taking Ca/Vit D supplementation. Don’t forget unusual sources of calcium like nicotine gum; also betel nut chewers from East Asia (though obviously a rare population here in Philly)

Pathogenesis of MAS

  • dietary input of calcium exceeds excretory capacity (thought to be >4-5g Ca/day, but varies widely)
  • Alkalosis further decreases Ca excretion
  • Ca leads to natriuresis and diuresis
  • pre-existing renal insufficiency and failure to suppress calcitriol levels play a role
  • Other meds play a role: NSAIDs, ACEIs, thiazides

The hallmarks of milk alkali syndrome are 1) hypercalcemia, 2) metabolic alkalosis and 3) varying degrees of renal failure. Note that these findings really exist on a continuum (acute, subacute, chronic)

Symptoms of MAS

Early signs: N/V, anorexia, distaste for milk, headache, dizziness, vertigo, apathy, and confusion
Chronic signs: myalgias, psychosis, tremor, polyuria, polydipsia, pruritus, and abnormal calcifications (band keratopathy, soft tissue, etc)


  • A careful history identifying heavy calcium and alkali intake is key
  • Lab findings: hypercalcemia (can be severe), AKI, metabolic alkalosis, low/normal phosphate, low 1,25-OH Vit D and PTH


  • Supportive: treat hypercalcemia, stop calcium/alkali containing supplements, stop NSAIDs, thiazides and other offending meds


Medarov B. The Milk-Alkali Syndrome. Mayo Clin Proc 2009.


1/11 VA report: anasarca, protein-losing enteropathy, ascites analysis

Thank you, Brandon Swed, for presenting an excellent and rich case of a older M->F transgender patient who presented with gross anasarca and ascites, and was found to have pulmonary hypertension that’s still being worked up.

We talked about mechanisms of edema formation, shown below:

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1) Increased hydrostatic pressure 2) Decreased plasma oncotic pressure 3) Increased capillary permeability 4) Decreased lymphatic drainage. Source: Symptom to Diagnosis: An Evidence-based Guide.

Edema is generally pitting, but some can be nonpitting:

  • Lymphedema
  • Thyroid myxedema

With thyroid myxedema, it is postulated that fibroblasts secrete water-loving glycosaminoglycans (GAGs) into the skin and soft tissues that then ‘vacuum up’ and retain water.

Why is myxedema usually nonpitting?

  • normally, edema water moves along tissue planes and is thus easily squeezed along the plane
  • but in myxedema, the water is more bound to the GAGs and less moveable, which is why it’s thought to be nonpitting

We also touched on ascites fluid analysis as a way of figuring out its etiology:

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Harrison’s Manual of Medicine, 18e. “Ascites”.

Lastly, for the wisecracks from the peanut gallery during our discussion of protein-losing enteropathy, there’s a dizzying number of causes of PLE, but here are some common culprits:

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Causes of protein losing enteropathy. Copland and DiBaise 2017.


Copland A and Dibaise J. Protein Losing Enteropathy: Diagnosis and Management. Nutritional Issues in Gastroenterology. April 2017.

1/10 VA report: large bowel obstruction

Today we discussed a 69 year old man who presented with abdominal pain and obstipation and was ultimately found to have a sigmoid volvulus.

Abdominal Pain
When considering causes of abdominal pain, always think about referred sources of pain
Thoracic causes
  1. Lower lobe pneumonia (get a CXR)
  2. ACS (EKG)
Pelvic Causes
  1. Ovarian/testicular torsion (careful testicular exam)
  2. Pelvic inflammatory disease (careful history and physical)
Think of surgical causes of abdominal pain early
  • Bowel
    • Perforation
    • Obstruction
      • Large bowel obstruction more likely to require surgery than small bowel disease
  • Vascular
    • Mesenteric ischemia
    • AAA rupture

If you’re concerned about perforation, start by getting an obstructive series, which consists of supine and upright KUBs as well as a left lateral decubitus film.

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Left lateral decubitus films allow air to rise over the liver, where it’s easier to see than if it were right next to the gastric bubble. Source: WikiRadiography

KUBs can detect as little as 1ml of air in the abdomen, but are still only 50-70% sensitive for intra-abdominal free air, so a CT is really the imaging test of choice.

This patient’s imaging revealed at first that he had a large bowel obstruction!

  • Large bowel obstruction
    • Causes: cancer, volvulus (sigmoid > cecal), less commonly: adhesions, diverticular strictures, IBD, intussusception, ischemic colitis strictures
    • p/w progressive abdominal pain, distention and obstipation
    • rapid onset distention/obstipation, slower onset nausea/vomiting (less common unless proximal obstruction)
  • Small bowel obstruction
    • Causes: post-op adhesions, malignancy, hernias, IBD, strictures, volvulus (less common)
    • p/w acute abdominal pain and nausea/vomiting
    • rapid onset nausea/vomiting, slower onset constipation/distention

Further testing revealed sigmoid volvulus, which is more common in African Americans and across the volvulus belt (Africa, Middle East, India, parts of Russia)

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Key differences in SBO and LBO management

  • SBO: can often be managed conservatively (NG tube, bowel rest)
  • LBO: may require GI input for endoscopic detorsion (if volvulus), and ultimately surgery given high rate of recurrence of sigmoid volvulus (70%), or if cause is malignant


Gingold et al. Management of Colonic Volvulus. 2012 Dec. Clin Colon Rectal Surg.

1/10 PPMC Report: Chylous ascites and small bowel obstruction

Today we discussed a really interesting case of a middle-aged gentleman with a longstanding history of lower extremity lymphedema and several months of chylous ascites of unclear etiology, who presented with 50 lb weight loss and was found to have a small bowel obstruction.

In working through this case, it is first important to understand: what is chylous ascites?

Chylous ascites means intra-peritoneal fluid with composition resembling lymphatic fluid. There are different criteria, but definitions generally require triglyceride level >200 mg/dL (some more conservative definitions use a level of 110 mg/dL). Presence of particles such as chylomicrons can also be suggestive of chylous fluid, as can an opalescent or white/milky appearance on gross examination (though this is not specific!).

There are a few general pathophysiologic mechanisms of chylous ascites formation:

1. Increased pressure in lymphatic system: When the pressure within the lymphatic vessels increases, the result is leakage down the pressure gradient into the peritoneal cavity. This causes chylous ascites. Persistence of this physiology can lead to deposition of collagen within the lymphatic vessels, which impairs absorption and can perpetuate the problem as well as causing a protein-losing enteropathy. This cycle can be caused by multiple conditions, including lymphatic obstruction, malignancy, retroperitoneal fibrosis, increased chyle production (can be seen in cirrhosis) and circulatory congestion.

2. Inflammation in the lymphatic system: Inflammatory mediators can cause increased permeability of lymphatic vessels, allowing for leakage of lymph into the peritoneal cavity. (This mechanism is similar to why sites of superficial inflammation appear edematous and red from leaky capillaries). Conditions leading to this outcome include certain infections, notably filiariasis, which is infection with the roundworm wucheria bancrofti. This entity causes dramatic lymphatic inflammation, which can result in a condition called elephantiasis in addition to chylous ascites.

3. Structural abnormality in lymphatic system: The lymphatic system can have either congenital or acquired structural abnormalities that predispose to leakage and development of chylous ascites. Congenital causes are rare. Congenital lymphangiectasia is a condition in which lymphatic vessels commonly lack valves necessary to support lymphatic flow, which can result in dilation, stasis, and leakage throughout the lymphatic system. Acquired causes include damage to the thoracic duct through trauma or as a post-operative complication.

Differential for chylous ascites includes (but is not limited to!):

  • GI tumors (particularly small bowel) including lymphoma, neuroendocrine tumor, Kaposi’s sarcoma
  • lymphangiomyomatosis
  • cirrhosis
  • tuberculosis
  • MAI (usually in HIV/AIDS patients)
  • wucheria bancrofti (filiariasis)
  • Whipple’s disease
  • post-radiation fibrosis
  • pancreatitis
  • constrictive pericarditis
  • nephrotic syndrome
  • sarcoidosis
  • retroperitoneal fibrosis
  • post-operative or traumatic¬†thoracic duct injury
  • dilated cardiomyopathy or RH failure
  • congenital lymphangiectasia

Our patient’s presentation was concerning for something luminal in the small bowel. Ultimately he was evaluated with push enteroscopy and biopsy of the jejunum, which showed lymphangiectasia, lymphedema, expansion of the lamina propria and small bowel mucosa. For this patient’s constellation of symptoms – starting with unexplained chronic lymphedema, then chylous ascites and a small bowel obstruction – congenital lymphangiectasia is a highly possible diagnosis. This condition can cause SBO by dilated lymphatics becoming large enough to block transit through the bowel, and sometimes lymph can thrombose in areas of stasis. This condition is generally managed with dietary changes (diet high in medium-chain triglycerides). Our patient is awaiting a lymphangiogram for further evaluation of the structure of his lymphatic system.

PPMC Report 1/4: Refugee Health Cases

Hi PPMC team!

Thanks for allowing me to pinch hit for Amy on a very snowy day! We were able to cover a LOT of ground — from the global refugee crisis and how the changes to the US policies regarding refugees impacts those attempting to come to this country to some interesting cases and common diseases seen among our refugee population.

Displaced people

As discussed, currently we have a record high share of individuals who are displaced from their homes. This is thought secondary to the number of conflicts, the extended duration of conflicts, and the fact that there are few long term solutions which means more people are in limbo.


We reviewed that while the number of refugees that have entered the US have waxed and waned over the years, until this year, we admitted individuals in proportion to the number displaced internationally. In fact, 2017 is the first year in which the United States decreased the number of refugees accepted into the country while the numbers of displaced individuals continued to climb. The Pew Research group notes that as of Oct 2017 only 28,000 refugees had been resettled in the U.S. which is far less than in 2016 where approximately 98,000 had been resettled. This is on track to accept just 0.2% of the world’s refugee population — which is much less than the historic average of 0.6% and even lower than the share admitted in 2001 and 2002 following the September 11th attacks (2). Even looking ahead to 2018, the Trump administration has proposed decreasing the refugee resettlement cap to 45,000 — down from 50,000 (2).


Additionally we covered several cases from our Refugee Clinic at Penn Center for Primary Care. We discussed the routine screening and testing performed in the clinic which is specific to the individual’s country of origin and then areas in which the lived in refugee camps.

We discussed the extremely common diagnosis of schistosomiasis and the international push to screen and treat everyone, especially young women — in an attempt to preserve fertility (4).

We also discussed Polio and the sequelae of prior infection. In addition to recognizing common complications of prior Polio infection, we discussed who needs boosters of their polio vaccine prior to travel — it’s approximately 25 countries — Not just the three with endemic Polio (Afghanistan, Pakistan, Nigeria)!


Lastly we discussed some complications of long term malnutrition including rickets. We discussed both Calcipenic Rickets and Phosphopenic Rickets and their respective lab abnormalities. Our patient likely had phosphopenic rickets based on lab findings, which in the US is most commonly secondary to renal wasting diseases or other genetic abnormality. However, in our Bhutanese refugee, her story lined up well for nutritional deficit which corrected with appropriate diet/supplementation.


  1. http://www.pewresearch.org/fact-tank/2017/11/02/how-u-s-refugee-resettlement-shifted-in-states-since-2002/
  2. http://www.pewresearch.org/fact-tank/2017/01/30/key-facts-about-refugees-to-the-u-s/
  3. http://www.unhcr.org
  4. WHO Department of control of neglected tropical diseases. Female Genital Schisosomiasis. http://www.who.int/schistosomiasis/en/

HUP report 1/3: Hyperthyroidism and Polyendocrine Syndrome

For today’s case, we presented a 24 year old male with no significant history who presented to the ED for 2 months of post-prandial nausea, weight loss, and loose stools.¬† He had seen GI doctors outside of our system and already had negative imaging, EGD/Colo, and intestinal biopsies.¬† His initial work-up in the ED revealed hyperthyroidism (TSH 0.01, tT4 16.07, tT3 2.13).¬† This is consistent with relatively mild disease (T4 and T3 < 2x ULN), and when Endocrinology was consulted, they were concerned that this level of hyperthyroidism did not explain his symptoms and that not all of his symptoms were consistent with hyperthyroidism at all.¬† A full endocrinologic work-up was pursued, and he was found to have autoimmune adrenal insufficiency as well (Addison’s disease).¬† This combination of hyperthyroidism and Addison’s disease clinched the diagnosis of polyendocrine syndrome type 2.¬† The key teaching points from the conference are as follows:

  1. Hyperthyroidism should be suspected when patients complain of symptoms such as jitteriness, diarrhea, palpitations, and weight loss; nausea is not a common feature.¬† Further history should be sought to look for signs of Graves disease (ex. Ophthalmoplegia), thyroiditis (pain), or masses.¬† A differential for hyperthyroidism is noted below, TSH-depended is crossed out because we know this patient has an appropriate TSH response to primary hyperthyroidism.CaptureAs you consider this diagnosis, the approach to narrowing your differential should follow the below algorithm.¬† Note that the TRAb and TSI antibodies can both be used for diagnosis and following response to therapy in Grave’s; our faculty expert prefers TRAb in her clinical practice.Capture
  2. Diagnosis of adrenal insufficiency should start with an am Cortisol.  If that value is > 12 you have ruled out AI, if it is < 3 then you have diagnosed AI; if it is between 3 and 12, then you should proceed with ACTH-stimulation to see if a value > 12 can be obtained with ACTH stimulation.  Once these first line tests are complete, you can differentiate primary and secondary dysfunction with an ACTH level. (As a contrast, hypercortisolism/Cushing is diagnosed with one of 3 options: midnight salivary cortisol, 24 hour urinary cortisol, or 1mg Dex supression test)
  3. The polyglandular syndromes are rare disorders.¬† They should be suspected when a patient presents with a rare endocrinologic presentation (such as Addision’s disease), but not when a patient presents with a common endocrinologic disorder (such as hyperthyroidism) unless the story is not adding up (as was the case here).¬† Details of the polyglandular syndromes are listed below.Capture