Paroxysmal Nocturnal Hemoglobinuria

Today we discussed a very rare cause of anemia and thrombosis, PNH.

This disease results from an acquired mutation in DNA encoding components of complement system, which leads to several clinical manifestations:

1) Hemolysis, which is episodic ("paroxysmal"). The degree of hemolysis depends on how many RBCs are abnormal. Unclear why it is sometimes nocturnal, as shown above. Chronic hemolysis can cause severe anemia, and renal failure from myoglobin-induced tubular damage

2) Thrombosis. It is unclear why patients with PNH are hypercoagulable; it may have to do with platelet abnormalities in PNH (all hematopoietic stem cells can be involved). Thrombosis is usually venous, but can be arterial. The hallmark is thromboses in relatively unusual places, most commonly portal vein or other intra-abdominal veins and cerebral venous sinus thrombosis.

3) Diminished hematopoiesis. Because marrow stem cells are involved, pancytopenia can be ther presenting manifestation.

Diagnosis: "PNH assay", which is flow cytometry for the clone of cells with abnormal complement-related proteins.

Therapy:

1) For hemolysis:
-supportive measures include transfusion, iron supplementation, folic acid supplementation.
-specific therapy is Eculizumab, a monoclonal antibody that inhibits complement activation, and significantly reduces hemolysis. Limiting factor is cost, estimated at $400,000 / year

2) For thrombosis:
-anticoagulation with heparin then warfarin as secondary prevention
-there may be lower risks of thrombosis on Eculizumab
-there is retrospective evidence supporting prophylactic anticoagulation with warfarin in selected patients

Stem cell transplant is also an option reserved as a last resort

Links:

Click here for the paper showing the effect of Eculizumab in PNH

Cocaine- medical complications

Today we discussed cocaine intoxication. Some points:

Acute intoxication:
Cocaine is a sympathomimetic, and acute intoxication presents with this toxidrome:
Hypertension, tachycardia, fever, flushing, diaphoresis, mydriasis, altered mental status, possibly seizures

The anticholinergic toxidrome presents very similarly. The 2 can be distinguished by:
-diaphoresis in sympathomimetic (vs. 'dry as a bone' in anticholinergic)
-more prominent hypertension in sympathomimetic

Management:
Besides the specific organ issues discussed below, general managment consists of
-benzodiazepines (mainstay!)
-if BP control is required, DO NOT USE PURE BETA BLOCKERS; this causes unopposed alpha agonism and makes hypertension/vascular effects worse; labetalol is safe in this situation (because it is both alpha and beta-blocker), and phentolamine or phenoxybenzamine are alpha-blockers that can be used.

Common specific organ effects (besides acute intoxication):
CNS- cerebral vasoconstriction, including stroke; movement disorders
CV- coronary vasospasm, which may cause MI; tachyarrhythmias, hypertensive urgency/emergency
Resp- perforated septum, smoking cocaine causes SOB, wheezing, chest pain hemoptysis in a large proportion of users. Acute fever, dyspnea, hypoxia, infiltrates soon after smoking has been called "crack lung"; is from alveolar damage. Interstitial lung disease is possible.

Recently recognized complication:
In the past year or so, there have been many recognized cases (including at this hospital) of patients presenting with agranulocytosis from cocaine "contaminated" with levamisole, an anti-helminth drug used in animals.

Click here for a summary of this complication

Click here for a paper from the Annals of Internal Medicine describing this. CMAJ has a similar report.

Dilated cardiomyopathy

Today we discussed causes of dilated cardiomyopathy,

Some etiologies of DCM:

1) Ischemia
This is the most common cause of cardiomyopathy in the developed world. Within the category of "initially unexplained" DCM, ischemia is less common, since this is usually the first etiology excluded.

2) Valvular heart disease
Some valvular lesions are compensated chronically by LV dilation- mitral regurgitation and aortic insufficiency are the most common (although NB- MR can follow DCM from dilation itself; this is often termed "functional MR"). End-stage aortic stenosis can also cause DCM

3) Infections
-Viral infections can cause myocarditis, which can lead to DCM. Coxsackie, adeno, echo are the most common. HIV is a recognized as a cause of DCM
-Chagas' disease (a protozoan infection) is most common cause of DCM in Central and South America.
-Lyme disease is associated with cardiac muscle dysfunction, although heart blocks are more common.

4) Toxins
-Alcohol; amount and duration correlate with risk
-Cocaine; may be independent of ischemia
-Anthracycline-based chemotherapy (usually takes a dose of 450mg/M2; each cycle has about 50)

-Trace elements. Rare cause; cobalt, arsenic, mercury... Click here for an interesting "outbreak" of cobalt-induced DCM in Quebec

5) Genetic

6) Peripartum CM- unclear cause; occurs in late pregnancy and early post-partum. Carries relatively good prognosis, but high risk of recurrence in subsequent pregnancies

7) Infiltrative CM's- hemochromatosis, sarcoidosis, amyloidosis

8) Tachycardia-induced cardiomyopathy. Prolonged tachycardia can cause reversible, sometimes severe, LV dysfunction

9) "Stress cardiomyopathy" AKA "Takotsubo" cardiomyopathy:
Rare, but increasingly recognized cause of LV dysfunction, with characteristic apical ballooning on 2D echo. May be associated with ECG changes including ST elevation. Sometimes associated with a stressful event (physiological or psychological); self-resolving. Click here for the origin of this term, the Japanese octopus trap...

In a significant proportion of cases, the cause remains idiopathic.

Links:

Click here for a recent NEJM review of DCM that goes over the evidence base for various pharmacologic and device therapies

Click here for a study looking at underlying causes and prognosis for initially idiopathic dilated cardiomyopathy.

Hyperthyroidism- physical exam

Today we discussed some of the physical exam findings of hyperthyroidism and how to diagnose a goiter

Hyperthyroidism
A general approach to the examination for hyperthyroidsm with some possible findings
General appearance: restless, anxious, thin
Vitals- tachycardia, atrial fibrillation, wide pulse pressure, fever
Eyes-
lid lag (superior sclera visible as patient looks down),
lid retraction, widened palpebral fissure
Graves' orbitopathy (see below)
CNS- fine tremor with hands outstretched, increased reflexes, proximal muscle weakness
CV- flow murmur
Abdo- increased bowel sounds
Extremities- warm, moist skin, velvety skin, pretibial myxedema (in Graves)
Associations: other autoimmune- e.g. vitiligo, adrenal insufficiency

A word about eye findings in hyperthyroidism
Some eye findings are general to all causes of hyperthyroidism (from increased sympathetic activity), and some are specific to Graves' disease.

Sympathetic
-lid lag
-lid retraction
-stare
-conjunctival injection

Graves orbitopathy
-EOM involvement
-lid edema
-exophthalmos
-loss of visual acuity

Evidence for how to diagnose a goiter:
Inspect and palpate
-look for lateral prominence = distance from imaginary line between cricoid and suprasternal notch to surface of thyroid gland
-Categorize as normal or goiter
-Subcategorize as small (1-2x) or large (over 2x) goiter

Ruling out a goiter:
Normal size by palpation (negative R 0.15)
No lateral prominence (NLR 0.41)
“Goiter ruled out” = normal thyroid size or gland not visible with neck fully extended

Ruling in a goiter:
Estimated size by inspection;/palpation
1-2x normal (positive LR 1.9)
over 2x normal (PLR 25)
Lateral prominence 0-2mm (PLR 3.4)
Lateral prominence > 2mm (PLR infinity)
“Goiter ruled in” = large goiter or lateral prominence over 2mm

Link:

Click here for link to JAMA Rational Clinical Examination for goiter (unfortunately, a special JAMA subscription is required)

Scleroderma

Today we discussed scleroderma (AKA systemic sclerosis)

This is a multisystem disesase of small vessels and skin/organ fibrosis

Epidemiology: Age 35-65, Female more common than male (7-12:1).

There are 2 types of systemic sclerosis- limited and diffuse

Limited SSc: sclerosis, thickening of distal limbs without truncal involvement. CREST fits into this category. Associated with anti-centromere AB. Calcinosis refers to localized hand masses on fingers/forearms. Telangiectasias are seen in face/mucosa/hands. Most serious manifestations of limited are pulm HTN, digital ischemia.

Diffuse SSc: thickening over distal and proximal limbs and trunk with significant organ involvement. Criteria are thickening of extremities proximal to MCPs or digital ischemia, pulmonary fibrosis. Edematous skin, painful joints, tendon friction rub, rapidly progressive skin fibrosis. Associated with SCL70 antibody.

Clinical:
Initially nonspecific; Raynaud's, fatigue, MSK complaints followed in variable time period by further sx (soon in diffuse, later in limited).
First specific manifestations are skin thickening, starting as swelling/puffiness over fingers/hands.
Subsequently variable; skin, pulmonary, cardiac, renal, GI involvement.

90% of SSc pts have Raynaud's and fibrosis of fingers, with loss of digital pads (sclerodactyly) and digital ulceration.

Skin: edema, tightness, decreased flexibility, contractures, then fibrosis.

MSK: arthralgias, arthritis, calcinosis, tendon involvement. Late: weakness/atrophy, possible overlap myosits

Pulm: Pulmonary fibrosis, PFTs show decreased volumes, diffusion impairment.

GI: small mouth, dysphagia, GERD/esophagitis. Loss of peristalsis

Cardiac: Myocardial fibrosis, myocarditis, diastolic dysfunction

Renal: Pathological change in most (small vessel vasculopathy); extreme is scleroderma renal crisis (acute kidney injury, with microangiopathic hemolytic anemia)

Therapy: No proven disease modifying agents; treatment is by organ system involved. In severe cases, immunosuppression may be used (e.g. steroids, methotrexate, cyclophosphamide)

Skin- key is moisturize, treat pruritus
Raynaud's- CCB, prazosin in severe
GI- treat GERD, prokinetics for paresis
Renal- ACE-I
Pulmonary- measures for pulm HTN

Links:
Click here for a recent NEJM review of scleroderma
Click here for a review from Rheumatology on scleroderma

Alcoholic hepatitis

Today we discussed alcoholic hepatitis.

This is distinct from chronic alcohol-induced liver disease, which causes steatosis and predisposes to fibrosis, then cirrhosis.

Alcoholic hepatitis is a clinical syndrome of jaundice and liver failure (usually after decades of over 100g/d intake). Patients have often stopped drinking for several weeks before onset. Female sex is a risk factor for this specific condition (with equal intake to men), but more men have the typical intake required.

Rapid onset of jaundice is the cardinal sign. Others include fever and ascites. Liver is typically enlarged and tender. Signs of chronic liver disease are often present.

Alcoholic hepatitis is a poor prognostic indicator; 40% of patients with severe alcoholic hepatitis die within 6 months

Diagnosis:
Lab: AST usually above 2x ULN, but rarely over 1000. ALT is lower. WBC count (esp. neutrophils), and INR are usually high. Renal failure (if it is hepatorenal syndrome) carries a poor prognosis.
Biopsy shows swollen hepatocytes with Mallory bodies. Cholestasis may be present.

Ddx includes NASH, viral hepatitis, drug-induced, fulminant Wilson's, autoimmune liver disaese, alpha-1, pyogenic abscess, cholangitis, HCC.

Severity indices:
Maddrey's discriminant function: [4.6 x (pt's PTT - control PTT)] + bili (mg/dL)
Value over 32 indicates severe alcoholic hepatitis; this is threshold for starting steroids.
MELD over 21- severe

Therapy:
General
salt restriction, diuretics, lactulose, thiamine, withdrawal tx as indicated. Tap for SBP
EtOH abstinence
Specific
Steroids: prednisolone 40mg/d x 4 weeks, then taper (or equivalent)
Pentoxyfylline- 400mg PO TID increases in-hospital survival; little head-to head data comparing to steroids; should be considered where there are contraindications to steroids.

Link:
Click here for a 2009 review from NEJM on alcoholic hepatitis that goes over the evidence for various therapies.