Adrenal insufficiency

In morning report we discussed two cases from the past that highlight an important diagnosis: adrenal insufficiency.

Both case examples were that of patients presenting with fatigue, lethargy, one patient had recurrent gastrointestinal infections and both were subsequently noted to have hyperpigmentation on exam and hyponatremia, and hyperkalemia.

Subsequent testing revealed primary adrenal insufficiency...aka Addison's disease.

First described by Thomas Addison in 1855, adrenal insufficiency is an important, life threatening, but treatable condition.

                                                                                                (Bornstein, SR, NEJM 2009)

The disease is best thought of by always referring back to the hypothalamic-pituitary-adrenal axis.

Recall that CRH is released from the hypothalamus that stimulates the anterior pituitary to release ACTH, that then stimulates the production of cortisol from the adrenal glands.

Differentiate Primary (ie adrenal disease) vs Secondary/Tertiary (ie pituitary/hypothalamic disease)

Primary adrenal insufficiency is due to destruction of the gland itself, DDx includes:

- autoimmune

- infectious (TB, Fungal, HIV)

- hemorrhage (coaguloapthy, Waterhouse-Friderichson post meningococcal disease, now recognized in other infections such as Staph)

- iatrogenic (medications that inhibit the axis, surgical removal of glands)

- genetic (CAH, Adrenoleukodystorphty, Adrenomyeloneuropathy)

Secondary includes:

- tumour

- apoplexy

- ischemia (ie Sheehan's syndrome)

- infiltrative disease

Symptoms:

Non specific symptoms of fatigue, weakness, lethargy, abdominal pain, nausea.

Physical exam:

Classically described as hyperpigmentation including but not limited to the buccal mucosa and teeth, elbows, creases, nipples.

Hypotension (especially treatment refractory hypotension)

Labs:

Electrolyte abnormalities (ie hyponatremia for both primary and secondary, hyperkalemia for primary). May also see acidosis, anemia, hypoglycemia, rarely hypercalcemia, as well as eosinophilia.

Screening:

AM cortisol if < 80 sensitive to rule out, if >  ~500-550 can rule in

If AM cortisol nondiagnostic, then next step would be an ACTH aka Cosyntropin stim test.

If normal you would expect to see an appropriate rise in cortisol in response to the administered Cosyntropin.

In primary you can measure ACTH levels and would expect them to be high due to the lack of cortisol and the continued stimulation due to lack of negative feedback.

High levels of ACTH, and inappropriate response to ACTH stim test = primary AI

In secondary, ACTH levels should be low. IF prolonged secondary AI, the adrenals will have atrophied due to lack of stimulation and so above test would be abnormal. IF it is early in the course of disease, or mild, then there still may be a normal response to the standard ACTH stim test.

Further testing to diagnose secondary AI

- low dose ACTH stim test. The thinking here is that if a tiny dose of ACTH stimulates a normal response, then it is very unlikely that the patient has AI, thus it is a sensitive test

- Insulin induced hypoglycemia (should NOT be done in patients with contraindications e.g. CAD, seizures). This test induces hypoglycemia and should activate the HPA axis.

- Similarly, a metyrapone test blocks 11-deoxycortisol conversion to cortisol. This again should activate the HPA axis and 11-deoxycortisol levels should go up if there is no disease.

- Lastly one can do a CRH stim test, essentially acting as the hypothalamus to try and stimulate the pituitary. This test can help to distinguish between hypothalamic disease and pituitary disease.

Once determined if primary vs secondary, next step is imaging (adrenals for primary, head for secondary).

Other clues to secondary that may lead to earlier imaging is neurologic symptoms such as headache, visual problems.

Principles of management

- treat underlying cause

- replace cortisol, and mineralocorticoids if primary

- stress in the right situations

Remember that in primary both cortisol AND aldosterone are low because the adrenal gland itself is damaged.

In secondary, cortisol is low because of low ACTH stimulating cortisol production, but aldosterone should be normal because the renin-angiotensin system is still intact. Thus more likely to see hyperkalemia in primary.

Both primary and secondary will have hyponatremia because of low ECFV, ADH release, water retention, and in the case of primary low aldo and salt wasting.

See this 1996 NEJM review article on adrenal insufficiency

And this more recent 2009 NEJM article that touches on predisposing factors, genetics, and has more info regarding culprit meds. The above image is from this 2009 NEJM article by Bornstein, "Predisposing Factors fro Adrenal Insufficiency".

"Oh by the way, I just started taking....."

The case today in morning report had multiple issues, but one that I wanted to discuss more was that of drug reactions. 

This patient was recently treated for a presumed UTI, and is now presenting with an acute elevation in her liver enzymes and a rash.

See this previous post in regards to the approach to transaminitis

This patient's history revealed that she was seen a week prior in the ER, diagnosed as having a UTI and treated with nitrofurantoin. In retrospect, 2 days after starting this medication she developed a rash over her chest, and ultimately was found to have a rise in her liver enzymes that subsequently started to improve once her medications were held. 

To complicate matters the patient was also taking PRN ibuprofen, as well as regular standing medications of tramadol, ASA, clopidogrel, a statin, and ezetimibe. 

Always consider the medications... whether prescribed, OTC, other sources. Careful history with precise timing is key to understanding IF a drug is the cause, and if so, which one. When considering a drug reaction, it is useful to carefully plot out the course of meds and the onset of symptoms/signs.

Remember that a simple exanthem is differentiated by a complex exanthem based on whether or not there is systemic organ involvement. Fever and elevation in liver enzymes are classic associated elements. (Impossible to know if fever played a role due to her antipyretic use).

Often, with multiple medications, it may be difficult to know exactly which is implicated, and often we simply don't know. If medications are ever reintroduced, remember (if possible) to do so one at a time to monitor for a reaction.

This case continues to be one in progress, but time will tell if this is all related to a drug reaction, or if other processes are at play.

See this nice review article from the perspective of a clinical pharmacist on drug induced rashes.

Also, a drug we do not often use...tramadol. See this CMAJ 5 things to know about tramadol article.

Fever and Back Pain

The case is that of a patient presenting with back pain and fever. 

As with every case in medicine, it is important to keep your thinking broad initially and based on the gathered data, to narrow your focus. 

Further history revaled that this patient had a 3 week history of lower back pain, increasing in severity and persistence. He is a known IVDU and had been using up until 2 weeks ago. He also had associated fevers and sweats, but no other localizing symptoms of infection or other system specific complaints.

Sidenote:

There are certain bacteria associated with what is mixed with IV drugs:

- Toilet water is associated with enteric gram negative bacilli

- Lime juice is associated with candida

On exam, he was febrile, but hemodynamically stable. His exam was significant for poor dentition with perigingival erythema. His MSK examination did NOT have any point tenderness over his spine.  The remainder of his physical exam was normal including no signs of systemic diseases/syndromes.

At this point, the differential for his back pain and fever included:

Infectious

- Vertebral Osteomyelitis

- Paravertebral/epidural abscess

- Pyelonephritis

- Intraabdominal infection with referred pain

Non-infectious

- Pancreatitis

- Malignancy ie bony mets, plasmacytoma, etc.

- Connective Tissue Disease

- Mechanical back pain

- Disc disease

MRI revealed L4-5 Vertebral Ostseomyelitis. Blood cultures were persistently positive for MSSA. ECHO is pending.

Dx: Vertebral Osteomyelitis secondary to MSSA bacteremia, presumed secondary to IVDU.

A word on Vertebral OM aka Discitis

Origin
- Hematogenous spread

- Direct inoculation (ie from surgery, trauma)

- Contiguous spread

Presentation

- Back pain is most sensitive, although may not have point tenderness. Severe point tenderness may suggest an abscess.

- Fever often not present (50-60%)...may also be because of use of analgesics/antipyretics

Micro

- Bacterial: Staph Aureus, E. coli, Salmonella (e.g asplenic patients at risk of encapsulated organisms), and others, all have a 'tropism' for bone. In men with GU infection, gram negatives are often implicated as the bladder venous plexus drains to the level of the spine. CNST and P.acnes should be considered if prosthetic/fixation devices present.

- Mycobacterial ie TB Pott's disease

- Fungal infections specifically dimorphic fungi

MRSA risk factors include: homeless, incarceration, previous MRSA, contact sports, hospitalization

Principles of management 

- Get micro either from blood or biopsy or abscess drain if needed.

- Unless patient is unstable, try to hold off on antibiotics until a bug is identified.

- Duration varies, but often will be 6 weeks

- Clinical follow up is required. CRP, MRI may be useful in the right context. 

Click here for a great review from the NEJM (The above image is from this NEJM article by Zimmerli W. N Engl J Med 2010;362:1022-1029).

Polyarthritis & Fever

Today was a case of polyarthritis & fever.

The pattern, timing, and associated symptoms of the polyarthritis will be key in narrowing the differential which includes:

- Rheumatologic conditions, specifically

Seropositive conditions: RA, MCTD, SLE, DM/PM

Seronegative condtions: AS, Reactive Arthritis (1st described in 1916 after Shigella dysentery in German officers), Psoriatic arthritis (often rash will appear after arthritis), and enteric arthritis

Systemic vasculitis

Crystal disease

- Infectious causes

Bacterial: Staph aureus, Group G strep, Neisserial infections

Tick borne disease ie Lyme disease (Borrelia burgdorferi)

Viral: Rubella, Parvo, HIV

- Drug related 

Serum sickness

This patient has a history of CAD, CHF, hypertension, hyperlipidemia, a. fib, gout, CKD, T2DM. He was on ASA, warfarin, bisoprolol, candesartan, glicliazide, lasix, and colchicine.

Gout can be precipitated by certain medications that cause hyperuricemia...think "CAN'T LEAP"

Cyclosporine

ASA

Nicotinic Acid

Thiazide

Lasix

Ethambutol 

Alcohol

Pyrazinamide

Remember that the ARB losartan actually has uricemic acid lowering properties.

Physical exam revealed symmetric painful and effusive joint disease affecting the shoulders, wrists, MCPs, PIPs, no DIP involvement, knees, and ankles.

Remember that 1st MCP and DIPs often in OA, 2nd MCP think of hemochromatosis, and wrist, MCP, PIP, knees, MTP's are the 5 most commonly affected joints in RA

Given the symmetric polyarthritis RA was considered the leading diagnosis. However, he did have proximal muscle weakness, which is not in keeping with RA, and raised the question of DM/PM or MCTD.

The diagnostic criteria for RA 4 out of 7 of the following, the first 4 greater than 6 weeks

1. Morning stiffness > 1 hour             5. RF positive

2. Arthritis 3 or more                        6. Rheumatoid nodules

3. Symmetric                                    7. Periarticular erosions 

4. Hand arthritis

At this time, diagnostic investigations are still pending.

Hopefully this provides an example and overview of polyarthritis and fever with some clinical pearls along the way.

Check out this review article on polyarthritis and fever from the NEJM. It is from 1994; however, it still provides a very nice general overview. Do keep in mind that certain aspects have since been updated.

The Terrible Lymphoma

Today in morning report we discussed a young patient who presented with pre-syncope.
The patient was otherwise well, but as part of the workup had a CXR that revealed an anterior mediastinal mass.

DDx of anterior mediastinal mass, 
brought to you by the letter "T"

Thymoma
Teratoma
Thyroid
Terrible Lymphoma
...and if lung parenchymal involvment, think of lung cancer

CT confirmed the mass with neck and supraclavicular lymphadenopathy.
No other involvement. 

Core biopsies were done and pathology showed Reed-Sternberg cells pathognomic for Hodgkin's Lymphoma. Remember an FNA is not enough, need core or excisional biopsy.

Staging was Stage IIA as per the Ann Arbor Staging:
I: one lymph node group
II: > one, same side of diaphragm
III: both sides of diaphragm
IV: extranodal involvement eg. bone marrow

All patients with lymphoma should be checked for HIV, Hep B and Hep C.


Hodgkin's Lymphoma is curable, has a bimodal age distribtuion.

Treatment regimens include ABVD chemotherapy, radiation for limited stage.

From an internist's perspective, important to know the cardiotoxicity of adriamycin, with cumulative dose being the biggest risk factor. This patient had a MUGA scan prior to starting therapy.

Also, bleiomycin can cause pulmonary fibrosis, and we discussed the interesting point that for some patient groups e.g. professional athletes, perhaps this side effect may dissuade them from including in their treatment regimen (famous examples in the past).

Fertility issues also need to be addressed prior to treatment.

Click here for a review on Hodgkin's Lymphoma from the Lancet.

ACS, risk stratification, and coronary CT angiography

We had a cardiology subspeciatly morning report today where we discussed an elderly patient presenting with a classical history for unstable angina. 

This patient twice had bypass surgery, and multiple PCI subsequent who now presents with worsening retrosternal chest pain both at rest and with minimal exertion increasing in intensity and duration with diminishing relief with nitro.

Investigations revealed no new ECG changes and serial troponins were negative; however given how 'good' the story was for ischemic heart disease, the patient was admitted and treated as ACS with consultation to cardiology for further management. 

In this particular case the patient stabilized in hospital with a plan to arrange angiography for potential symptom relief in the near future. 

This case though classic, raised a couple very interesting points.

To cath or not to cath:

This patient has obvious risk factors for coronary disease and a convincing history as such. However the point was raised as to how one would know (in the absence of potentially localizing ECG changes) where the target lesion was? Given his history of bypass and multiple PCI's, it is possible that he has multiple areas of potentially significant occlusion, but which exactly is the target would be difficult to know.

One strategy to address this would be to arrange a nuclear scan or stress ECHO prior to the angiography, with hopes of localizing the target area.

What about for less obvious cases?

We then discussed patients at lower risk for ischemic heart disease and to what extent they should be worked up.

Specifically we discussed coronary CT angiography (CCTA). There are multiple studies looking at CCTA including the Rule Out Myocardial Infarction Using Computer Assisted Tomography II (ROMICAT-II) from the NEJM in 2012. This study randomly assigned 1000 patients presenting with chest pain to either CCTA or standard evaluation (which may not have been any testing) and found that time from presentation in the ER to discharge was shortened with only slightly higher incurred costs. The downside was the increased radiation exposure from the CT. 

This study along with others support that CCTA is a useful rule out test in patient with low-intermediate risk for acs, though at the cost of radiation exposure (though now with better technology the amount radiation is lowering).

One important question, is whether any further testing is required at all for low-intermediate risk patients. One could argue that in these patients, given their low risk profile, that they could be safely discharged without any further testing.  These factors and more need to be considered when weighing the risk/benefits/costs of further testing such as CCTA in evaulating this subset of patients. 

Click here for the NEJM article

Pancytopenia and Splenomegaly

Today we discussed a case of pancytopenia.

Click here for a previous blog and here for differentials of pancytopenia based on marrow cellularity.

In general, it is still a useful approach to consider causes based on the premise of decreased production, which include primary marrow disorders such as malignancy, fibrosis, storage disease, as well as myelodysplasia and aplastic anemia (congenital or acquired including viral illness parvo b19, ebv). Nutritional deficiencies such as B12 and Folate, as well as sepsis are other reasons for decreased production leading to pancytopenia.

Our patient was feeling generally unwell with persistent nausea and vomiting and constitutional symptoms. 

Physical exam was significant for splenomegaly.

CT imaging showed mediastinal adenopathy, and confirmed the presence of an enlarged spleen.

Sidenote:

The causes of massive splenomegaly (spleen >1000 g):

• infectious: visceral leishmaniasis (kala-azar), malaria
• myeloproliferative: CML, myelofibrosis
• malignancy: primary lymphoma of spleen

Bone marrow aspiration was unsuccessful; however peripheral blood film showed atypical lymphocytes, and flow was consistent with a B cell lymphoma. 

The patient will be followed up as an outpatient to facilitate formal tissue diagnosis, staging and subsequent management. 

Quick word on hematologic malignancies:

Lymphomas are classically subdivided based on Hodgkin's and Non-hodgkin's lymphoma. 

Within NHL, most helpful to think of in terms of indolent (e.g. follicular, marginal zone, mantle cell) and aggressive (e.g. DLBCL), and very aggressive (e.g. Burkitt's lymphoma)

As a general principle, indolent lymphomas are not curable, but slow growing, and aggressive lymphomas are curable, but as the name implies, more aggressive.

Treatment will likely consist of chemotherapy and steroids. Because the patient will be immunosuppressed, the last point of the day was to remember to consider latent infections and so to screen for:
- TB
- Hepatitis B
- HIV
(- Strongyloides which can in the face of immunosuppresion can lead to disseminated hyperinfection)

Renal failure in prostate cancer

Quick post today - we discussed a case of a an elderly male with metastatic prostate cancer refractory to treatment who presents with an acute rise in creatinine 1118 from a baseline of 70. Given his history of prostate cancer urinary obstruction either at the level of the prostatic urethra, or higher at the level of the ureter, potentially from retroperitoneal masses, was the leading diagnoses. Foley catheter insertion yielded less than 50 cc of urine.
Physical examination was significant for a large palpable, firm abdominal mass spanning his upper abdomen. He also had asterixis and decreased LOC. Imaging showed a 15x20x20 cm retroperitoneal mass causing bilateral hydronephrosis. He was treated with nephrostomy tubes.

Always be aware of post-obstructive diuresis, that can occur after relief of obstruction. Often this is an appopriate diuresis as retained urea is expelled causing an osmotic diuresis, as well excess salt and water from the obstruction is also diuresed. However, this can persist leading to hypovolemia. Monitor urine lytes and replace urinary losses.

The question raised was whether he require bilateral or unilateral nephrostomy tubes to relieve his obstruction. There is little evidence to guide therapy of post renal obstruction in metastatic prostate cancer. In 2009, Nariculam et. al published a study in The British Journal of Radiology where they looked at 25 patients with metastatic prostate cancer presenting with acute renal failure from obstruction. 18 underwent bilateral neprhostomy tube insertion, and 7 underwent unilateral insertion. Ultimately there was no difference in recovery of renal function and overall no difference in mortality, suggesting that survival is based on the aggressiveness of the prostate cancer rather than the insertion of one or two nephrostomy tubes. 
Multiple issues need to be balanced in practice. There is the risk of complication with tube insertion and so if one is sufficient than why insert two? However, as this study showed, some tubes can become blocked, or one kidney may have sustained significant injury and not recover function and if kidney function fails to improve after one insertion, then the patient may require a second insertion anyways.

The article can be found here

For a recap of AKI see my post from July here

Sidenote, interesting examples of uremic frost:
One from the CMAJ and another from the NEJM

Uremic frost occurs in advanced renal failure with deposition of urea and other nitrogenous waste products that crystallize on the skin. First described by Hirschsprung in 1865

Is it just me...or is it warm in here?

In morning report today we discussed the case of a patient who was transferred to TGH from a peripheral hospital presenting with fatigue, dyspnea, jaundice, and anemia.

Ultimately DAT was positive and diagnosed as having Warm Autoimmune Hemolytic Anemia.

Clinically the patient looked well initially, but within a 12 hour timeframe condition deteriorated with a starting hemoglobin of 97 that dropped to 33. Unfortunately despite treatment with steroids, IVIG, and RBC transfusion given severity, the patient passed away. This case will leave us with unanswered questions, but does remind us of how quickly things can deteriorate especially when the underlying cause of the AIHA is unknown. 

We will discuss anemia, and more specifically the diagnostic approach to hemolytic anemias with management considerations.

The approach to anemia is a 'bread and butter' medicine topic and so very quickly (non-exhaustive):

Think micro, normo, macrocytic.

Microcytic anemia "TAILS"

• Thalassemia: alpha, beta. Clue is markedly low MCV
• Anemia of chronic disease: Due in part to hepcidin release that imparis iron utilization
• Iron deficiency*: always find out why they are iron deficieny (intake, absorption, loss)
• Lead poisoning
• Sideroblastic anemia
• ...and porphyria should be in DDx

Macrocytic anemia

• Active blood loss, and hemolysis initially can have macrocytosis
• Megaloblastic (ie DNA synthesis problem)
• B12, folate, drugs (eg methotrexate, AZT, HU)
• Non megaloblastic
• Etoh, liver disease, hypothyroidism, MDS

Normocytic anemia
Decreased retics (marrow problem)

• combined iron and b12/folate deficiency
• anemia of chronic disease
• marrow replacement (fibrosis, malignancy)
• aplastic anemia
• pure red cell aplasia

Increased retics (meaning marrow is working overtime)

• Active blood loss
• Hemolysis

Approach to hemolytic anemia

Intrinsic RBC

• RBC membrane (e.g. spherocytosis), Hemoglobin disorder (e.g. SCD, thal), Enzyme deficiency (e.g. G6PD, PK deficiency) 

Extrinsic RBC
Non-immune 

• MAHA: TTP, HUS, DIC, Malignant HTN, HELLP, Scleroderma crisis
• Macroangiopathy: Mechanical heart valves

Immune

• Warm (IgG +/- C3d)
• primary or secondary (malignancies ie CLL, CTD, meds including fludarabine, interferon)
• Cold (IgM)
• primary or secondary (lymphoproliferative disorders, CTD, EBV, Mycoplasma)
• Paroxysmal cold hemoglobinuria (IgG and C3d)

Management considerations for Warm AIHA

Get help: hematology, transfusion medicine
Identify, if possible, the cause of the AIHA and treat appropriately
Transfuse only if life threatening anemia. Alert blood blank if transfusion required
Limited evidence exists for treatment and is largely expert opinion
Steroids are first line
Second line include splenectomy, rituximab
Some evidence exists for the use of different cytotoxic agents
Unclear evidence for IVIG, plasma exchange

See this review on the treatment of warm AIHA specifically

Also, this article on general treatment approaches to AIHA is very helpful.

"Blood glucose over 1000!!!........mg/dl"

Ok so it's more impressive using mg/dl, but using SI units, it's actually 67 mmol/L. But still very high!!

This was the case we discussed in morning report today.

An elderly patient who was sent in to the ER by their family doctor due to an elevated blood glucose.

Context is everything and if this were a young patient or a patient with the right 'metabolic' characteristics we would think of a first presentation of T1DM or T2DM respectively.

However, this patient has no history of diabetes and in fact routine physical as recent as 2012 revealed a normal fasting blood glucose.

Already this patient dose not fit the right picture for a new diagnosis of T2DM and so we discussed the most likely explanation for this patient, and decided at some point, we would like to investigate the pancreas (malignancy?).

We went through the exercise of anticipating his symptoms as a result of his hyperglycemia, and predicted correctly so, that he would have lethargy, fatigue, polyuria/polydipsia, decreased appetite, weight loss, abdominal pain, nausea/vomiting, blurry vision, paraesthesias, and also considered mental status changes (which were absent).

His physical examination revealed a mild postrual drop, but more importantly he was symptomatic from supine to standing, and his JVP was flat all pointing to volume contraction.
He was also icteric, with no abdominal findings that further supported our initial thoughts.

Lab investigations revealed a serum glucose of 67, no anion gap, normal electrolytes (inlcluding a K of 5.0). Ketones were negative.

HHS (Hyperglycemic Hyperosmolar State)

Differs from DKA in that DKA is an absolute insulin deficiency that is associated with ketosis.
HHS is a relative insulin deficiency that can be associated with ketosis (hence the change to HHS from HONK)

General principles of treatment (not inclusive)

1. Hyperglycemia requires FLUIDS 
2. Acidemia requires insulin

3. Watch the K as insulin will shift and lower. 

Flow charts are key in charting fluids, BG, insulin, AG, Na, K, HCO3.

Back to the case. This patient require 8 L of fluid overnight, received insulin therapy and within 24 hours his blood glucose had normalized and he was euvolemic.

BUT, bili was 90, his liver enzymes were elevated consistent with obstruction, and a CT revealed a pancreatic mass.

His diagnosis is likely to be pancreatic CA and is going for ERCP for decompression and biopsy.

See this 'classic' CMAJ article on the diagnosis and treatment of DKA and HHS.

Also check out  the JAMA RCE on hypovolemia