Horses and Zebras

Wednesday, August 12, 2015

Dyspnea and Interstitial Lung Disease

Today's case was of a 46-year-old man presenting with a 4-6 week history of disabling progressive dyspnea, pleuritic chest discomfort, weight loss, night sweats, and dry cough. He had a medical history of asthma which seemed to be well-controlled, and possible ulcerative colitis investigated, but without any follow up or established diagnosis. His physical examination features dry “Velcro” sounding crackles consistent with interstitial lung disease. His chest x-ray was abnormal which led to a CT scan demonstrating ground glass opacification.

There were multiple learning points today:

-Night sweats (in contrast to the type of sweating that many people experience) are characteristically drenching and require changing of clothes/sheets overnight. It is helpful to phrase the question this way when taking a history to increase the specificity of the question.

-Drenching night sweats are often associated with tuberculosis but have a differential diagnosis that includes malignant processes (Hodgkin’s and Non-Hodgkin’s lymphomas can both produce this) and autoimmune/inflammatory causes.

-We talked about congestive heart failure as being a possible etiology for this man’s dyspnea. In addition, if he had pulmonary venous thromboembolic disease for a long enough duration he’d be able to develop pulmonary hypertension which could lead to cor pulmonale and right-sided decompensated heart failure. We also talked about pleuritis and pericarditis as manifestations of his presumed ulcerative colitis which could lead to pleural effusions and pericardial effusions +/- tamponade.

-We talked about pheochromocytoma, a rare tumour of the adrenal medulla which secretes catecholamines and can lead to hypertensive emergencies. These tumors are classically associated with the “3 P’s” of Pounding (headache), Palpitations (from hypertension/tachycardia), and Pallor (from excessive vasoconstriction due to catecholamines). They are also a secondary cause of hypertension and can be diagnosed by finding abnormal amounts metanephrines and catecholamine byproducts in the urine. Like people intoxicated with cocaine, you should never give these people beta-blockers because it leads to an “unopposed alpha” phenomenon with a paradoxical increase in blood pressure as a result of the beta blockade.

-We discussed that this may be intrinsic lung disease related ulcerative colitis as well as treatment of inflammatory bowel disease.

-We discussed briefly what sounds like alphabet soup – Cryptogenic Organizing Pneumonia (COP) and Broncioloitis Obliterans with Organizing Pneumonia (BOOP). These are similar clinical entities with the main difference being that there is an identifiable cause in BOOP (secondary organizing pneumonia). They are both organizing pneumonias with a variety of possible causes.

I have included two reviews of the extra-intestinal manifestations of IBD, as well as one focusing on the pulmonary manifestations of IBD. I have also included a review of cryptogenic and secondary organizing pneumonias.

Hypercalcemia and Multiple Myeloma

Today's morning report case was very interesting and tied together a number of diagnostic and management entities seen commonly on our wards.

The case featured a 72-year-old man who was brought into hospital for polyuria for around one week’s duration. Upon further questioning, the polyuria preceded polydipsia, and he had an unquantified amount of weight loss, some bony pains, and alterations in mental status/confusion. His physical examination was remarkable for volume contraction, but an absence of lymphadenopathy or any signs of endocrinopathy. His initial bloodwork showd a mild macrocytic anemia, leukocytosis with a lymphocytosis, significant acute renal injury with a creatinine of 180umol/L, and profound hypercalcemia of 4.01mmol/L corrected. His serum phosphate was elevated at 1.6mmol/L. Chest X-ray demonstrated rib fractures. Based on the suspicion of a clonal plasma cell disorder, a serum and urine protein electrophoresis was sent, which yielded negative results. A serum free light chain assay was then sent which showed an abnormal ratio. The patient’s peripheral blood was sent for flow cytometry which showed a clonal population of T-cells consistent with HTLV-1-mediated adult t-cell leukemia-lymphoma. Because the T-cell population wouldn’t explain the free light chains (but may explain the hypercalcemia), he may have both a plasma cell disorder and a t-cell disorder.

Despite the seemingly complex nature of the case, there were multiple learning points:

-One of our trainees pointed out correctly that, in a patient with multiple “non-specific” findings that do not seem to relate to a single organ, a systemic process should be suspected. These often include endocrinopathies (thyroid disease, adrenal disease), hypercalcemia, and renal failure.

-Hypercalcemia has a wide differential diagnosis. The first step is to differentiate whether the process is PTH-dependent or not, which can be done by ordering a serum intact PTH level. If the PTH is elevated (or even normal) in the presence of hypercalcemia, that is inappropriate and suggest a PTH-mediated process like primary hyperparathyroidism (adenoma, MEN syndromes, etc) or familial hypocalciuric hypercalcemia (FHH). If the PTH is low (suppressed appropriately) then the process can either be malignant, related to granulomatous disease (through excessive 1-a-hydroxylase activity and hypervitaminosis D), or related to exogenous Vitamin D overdose. In the malignant realm, it is helpful to differentiate between causes related to solid tumours (direct bone destruction or humoural effects such as PTH-related peptide secretion) and hematologic malignancies (direct bone involvement as in multiple myeloma, or humoural effects due to 1-a-hydroxylase activity in lymphoma cells).

-Hypercalcemia produces high urinary losses through multiple mechanisms. The least significant is osmotic, but it also affects the NKCC channels producing a “Lasix-like” effect and produces a nephrogenic Diabetes Insipidus which may lead to hypovolemia and dehydration.

-The treatment of hypercalcemia involves fluids. Resuscitation fluids like normal saline will act to expand plasma, diluting the calcium. They will also increase renal calcium delivery, and distal tubular sodium delivery allowing it to be exchanged with calcium. Diuretics should only be given if patients are volume overloaded and it will allow increased fluid delivery.

-Multiple Myeloma exists in a continuum of diagnoses of clonal plasma cell disorders. Secretory B-cell clones produce immunoglobulins which may lead to a clonal “spike” on a serum protein electrophoresis. This “M-spike” can be quantified. The clinical consequences of myeloma are the CRAB features (hypercalcemia, renal failure, anemia, and bony lytic lesions). A clonal spike associated with CRAB features is diagnostic of multiple myeloma. A clonal spike without CRAB features is either MGUS (Monoclonal Gammopathy of undetermined significance) or Smoldering Multiple Myeloma depending on whether there is more than 30g/L M-protein and whether there is more than 10% clonal plasma cells in the bone marrow. The clinical significance of this is the annual rate of progression to multiple myeloma. The newest myeloma definitions state that, whether CRAB is present or not, greater than 60% marrow infiltrated with plasma cells is a “myeloma defining event.” Keep in mind that not all myeloma is secretory meaning that there may be no SPEP. Also, the quantities of the M-spike may be insufficient, in which case a serum free light chain ratio can be helpful in detecting a clonal B-cell disorder. Finally, AL amyloidosis does not necessary indicate multiple myeloma per se.

Postobstructive Pneumonia

The case today involved a 68-year-old man with a history of COPD, untreated lung cancer (metastatic), and schizophrenia who lives in an assisted-living facility. He was brought to to hospital for a two-day history of fever and dyspnea. His imaging revealed a densely consolidated right lung with a loculated pleural effusion, as well as findings of obstructive lung disease in the other lung. Additionally, he had obliteration of his entire right main bronchus by tumour. His blood culture was positive for S. pneumoniae. He was treated with oxygen and antibiotics, with a palliative treatment intent.

Learning points:

-It is helpful to begin generating a differential diagnosis immediately upon hearing the “chief complaint.” This will help frame the questions that you are going to ask, and even frame the way that you obtain the past medical history. As an example, if this patient had come in with an allergic reaction, his COPD severity is less important in the clinician’s mind than it is when he presents with dyspnea and fever.

-When evaluating patients, always obtain their medical history and the medications that they take. There is a large prescribing bias towards keeping people on what they were on, even though many clinicians would advocate for stopping medications that we cannot identify a good cause for – examples frequently include proton-pump inhibitors, iron supplementation, cholesterol medications in the frail elderly, dual antiplatelet therapy, etc. If their medical history does not match up to their medications, our job is to make a reasonable attempt at correcting that.

-Patients with lung cancer who present with dyspnea are usually going to have one of four things: consolidated lung (pneumonia), bronchial obstruction, pleural effusion, and pneumothorax.

-Fever can be present in these patients for a variety of reasons including as a result of the tumour itself. That said, in the case of a fever with a consolidated lung as a result of obstruction, treatment with antibiotics may be warranted after obtaining cultures.

-Treatment of lung cancer is rarely with a curative intent. We talked about the types of lung cancer (small cell and non-small cell) and that small-cell generally portends a worse diagnosis. Treatment options for these patients can include simple interventions like palliative oxygen. Systemic treatments like chemotherapy and steroids (in the right setting) may alleviate or shrink tumours and re-open airways. Radiation is another option that may have relatively minor risks. Finally, thoracic surgery can occasionally “stent” open airways as a result of tumours, but they are relatively selective to whom they offer this.

Resources for further reading:

Hsu-Kim, C., Hoag, J. B., Cheng, G. S., & Lund, M. E. (2013). The Microbiology of Postobstructive Pneumonia in Lung Cancer Patients. Journal of bronchology & interventional pulmonology, 20(3), 266-270.

Thursday, May 21, 2015

Glomerular Diseases

Everyone has a different approach to this problem and categorizes diseases in different ways. It is important to choose one classification system and stick with it. What can be confusing about the Nephritic vs Nephrotic diseases is that there is significant overlap in their presentations, including the degree of proteinuria seen in disease.

Here is a helpful and simple approach to the problem:

Now I will elaborate on these diseases using the above approach:

NEPHRITIC Diseases

1. Immune Complex (Granular IF)

Pearl: IgA nephropathy is synpharangyitic (occurs at the time of pharyngitis) whereas post-strep GN is postpharyngitic (occurs 2 weeks after pharyngitis)

Low Complement

Post-Streptococcal Glomerulonephritis

Usually exhibit low amount of urinary protein
Present with hematuria with or without RBC casts.
Low C3, Normal C4; ASOT+; Anti-DNAse B+
Treatment is supportive – usually resolves in 3-4 weeks

Membranoproliferative

o Type I - HCV/HBV/SLE/IE/Cancer/Sjogrens

C3 may be normal; C4 low

Cryoglobulinemia - Type II

o Low C4; C4 normal

Treatment: Rituximab and cyclophosphamide

SLE

C3 and C4 low
Class III/IV
There are 6 stages of Lupus nephritis – Stage III and IV (focal proliferative and diffuse proliferative) are categorized here. This stage is treated with steroids, MMF, and cyclophosphamide
In general, biopsy is indicated in lupus nephritis when complements are low, active urinary sediment, and with a positive anti-dsDNA
All patients should be on ACE inhibitors to target proteinuria of less than 1g per day, and a BP of less than 130/80 and have dyslipidemia management.

Infective Endocarditis
Cholesterol Emboli

Rarely spontaneous, usually occurs following a procedure manipulating large vessels
Other manifestations include purple toe syndrome and livedo reticularis.

Normal Complement

IgA Nephropathy

Gross hematuria 1-3 days after URTI.
First line therapy is non-immunosuppressive therapy:

ACE inhibitors
+/- fish oils

Starts systemic steroids if:

Increasing creatinine (not for stable, elevated creatinine)
Protein >1g/day
Active kidney disease on biopsy

HSP – Henoch-Schönlein Purpura

Associated with IgA nephropathy
Associated with palpable purpuric rash
May also present with mononeuritis multiplex
Generally seen in younger patients
Occurs in older patients as a paraneoplastic syndrome in MDS
Treatment generally supportive, may include steroids

2. Anti-GBM (linear IF)

Presents with RPGN (Rapidly progressive GN)
40% of patients have ANCA positivity as well
Goodpasture’s Disease is the term used when GN is associated with lung hemorrhage – occurs in 50% of patients. Anti-GBM Disease means there is no lung involvement.
Treatment:

Pulse steroids, cyclophosphamide, plasma exchange therapy
Who to treat:

All patients with pulmonary hemorrhage
All patients with kidney involvement who do not require dialysis
Selected patients on dialysis: those with lung involvement or with systemic vasculitis (ANCA)

Duration depends on disappearance of anti-GBM
Taper medications over 3-6 months
Patients on dialysis are often not treated – their kidneys are too damaged and therapy will not benefit them

3. ANCA (Pauci Immune)

All three of these diseases affect both the lungs and the kidneys and therefore may present with hematuria and hemoptysis

GPA (Granulomatosis with Polyangiitis)

Anti-PR3 (cANCA) positive
Present with saddle nose deformities, nasal polyps
May also have salivary gland involvement
Treat with pulse steroids, cyclophosphamide, maybe PLEX

EGPA (Eosinophilic Granulomatosis with Polyangiitis)

antiMPO (pANCA) positive
Also presents with neuropathies and may occur with asthma

MPA (Microscopic Polyangiitis)

antiMPO (pANCA) positive
Open lung biopsy is the best way to diagnose MPA

NEPHROTIC Diseases

Each cause of nephrotic syndrome may be primary or secondary to an underlying disease process
Generally, the treatment for these diseases includes ACE inhibitors/ARBs and treating the underlying cause of the disease
If primary disease (and therefore no underlying cause) - use steroids for treatment.
Complications:

Thrombosis – this is due loss of ATIII and Protein C/S in the urine
Infection - this is due loss of immunoglobulins in the urine; leads to infection by encapsulated organisms
Dyslipidemia – due to overproduction of LDL and VLDL
Edema – due to low oncotic pressure (loss of protein) and subsequent activation of the RAAS system

1. Minimal Change Disease

o Most common cause of nephrotic syndrome in children

o Most cases are idiopathic

o Secondary causes include NSAIDs, Hodgkins/lymphoproliferative disorders, and leukemias.

2. Focal Segmental Glomerulosclerosis (FSGS)

o Most common cause of nephrotic syndrome in adults

o Can be thought of as a more severe form of Minimal Change Disease

o Often asymptomatic except for hypertension

o Secondary causes include HIV, lupus, sickle cell disease, heroin, urinary reflux, and obesity

o FSGS is slowly progressive

o Notable variant is HIV associated nephropathy (HIVAN) – this is a collapsing variant of FSGS. It is treated with HAART and ACE inhibitors; may transplant

3. Membranous Nephropathy

o Second most common cause of nephrotic syndrome in adults

o Most cases are idiopathic (>80%)

o Immune complex mediated diseases

o Rule of thirds with prognosis – one third will resolve, one third will worsen, and one third will have chronic changes

o Treated with ACE inhibitors

o Secondary causes:

o Hepatitis B, Hepatitis C, Syphilis

o Malignancy – lung and colon

o Drugs used to treat RA (Gold, Penicillamine, NSAIDs, etc.)

o SLE Stage V. Indications for immune suppression (steroids + cyclophosphamide or cyclosporine):

Persistent severe and symptomatic nephrotic syndrome (proteinuria persists >3.5g/d)
Increased or rising serum creatinine
Mixed membranous and proliferative lesions on biopsy

4. Nodular Disease

o Diabetic Nephropathy – the most common cause for end-stage renal disease and dialysis in North America

o Amyloidosis – In AA disease (secondary to an inflammatory disorder, such as Rheumatoid Arthritis), the kidneys are involved in nearly in all patients.

Sorry for the long post. Here's a potato: