Digoxin Sensitivity and AL #Amyloidosis

Last week, I learned something. Since learning new things is a good habit to get into, I thought I'd share - especially since the pertinent data were actually a little difficult to track down. 

A patient of mine with long-standing AL amyloidosis was admitted to the hospital with congestive heart failure occurring in the setting of rapid atrial fibrillation ("AFib"). For non-medical folks, this means the top chambers of the heart  (the atria) were beating extremely fast and irregularly, driving the bottom part of the heart (the ventricles) to do the same. This is not a kind thing of the atria to ask of the stiff, thick, amyloid-filled ventricles. 

The situation was particularly difficult because of the patient's chronically low blood pressure.  His typical BP of 90/50 was running even lower due to the abnormal heart rhythm.  Some of the medications one might normally employ to control the Afib - like beta-blockers or calcium channel blockers - could not be used here because of the BP.  I suggested to the medical residents that we try using digoxin, which would not be expected to lower the blood pressure.  An hour later, the team called me back to let me know they had decided against that because the risk of digoxin toxicity was too high in this patient. I asked why they felt he was at risk for this, and the answer surprised me.

"His amyloidosis."

A search of PubMed using the search terms "digoxin" and "amyloidosis" yields only 8 references, at least as of the afternoon of May 18th, 2013. Of these, one of them was a case report of a person who was diagnosed with cardiac amyloidosis after developing fainting spells on digoxin.  Another article describing two cases of familial transthyretin (ATTR) mentions in the abstract that such patients are prone to digoxin toxicity, but does not state that the patients in that report experienced this. I have thus far not been able to track don a copy of the actual article text. The other 6 references that came up were not relevant to my specific patient's case. 

I tried another strategy and pulled up a review from cardiac amyloidosis guru Dr. Rodney Falk. Here is his commentary on the use of digoxin in AL amyloidosis patients: 

"There is no role for digoxin in patients with cardiac amyloidosis who are in sinus rhythm. However, for patients with atrial fibrillation, cautious use of digoxin may aid in heart rate control although the risk of digoxin toxicity may be increased, possibly related to abnormal binding of the drug to amyloid fibrils."

A reference for last statement not provided, so more digging was needed.  Turned up the following additional references, not identified by original search:

A 1961 article from one of Michigan's own in the Annals of Internal Medicine which described two amyloidosis patients who seemed to have problems stemming from digitalis (a drug structurally related to digoxin, but with a longer half-life in the blood: 5-7 days, compared to 1.5-2 days). Pt #1 was a 58-yo farmer with jaundice and hypoalbuminemia (low serum protein levels) and atrial fibrillation who developed severe bradycardia (slow heart rate) of approximately 30 beats per minute after a 0.8 mg loading dose of digitalis followed a couple of days later by a 0.1 mg dose. Although it is not entirely clear from the text, it appears the patient had a liver biopsy proving he had systemic amyloidosis a few days before dying of liver failure.  No information was provided regarding kidney function. On autopsy, multiple organs were confirmed to be infiltrated with amyloid, including the heart. Amyloid fibril typing was not performed.  Pt #2, on the other hand, almost definitely had AL amyloidosis complicating a plasmacytoma. She was in sinus rhythm but had symptoms of congestive heart failure and exam findings suggesting cardiac tamponade (compressive fluid around the heart). She was treated with 1.3 grams of an older digitalis preparation (digitalis folia) over 60 hours. I cannot find a good reference with a dosage equivalency table to put this into current medical context. Also, again, no information on kidney function was provided. After dosing, the patient developed cardiac bigeminy (paired heart beats) with a rate of 70 beats per minute. The patient then developed severe hyperkalemia (high serum potassium levels - 8.3 mEq/L in this case, or about twice the normal level, after originally starting in the normal range). The patient suffered heart rhythm disturbances typical of this potassium level, and she died. On autopsy, the patient was found to have cardiac amyloidosis and a pericardial effusion (fluid around the heart) was confirmed. In 1961, serum digitalis levels were not obtainable.

A second article from A. Pomerance of London's Central Middlesex Hospital's Department of Morbid Anatomy and Histology was received at the British Heart Journal on Aug 17th, 1964, and was ultimately published in 1965. It turns out that at the exact same time, the Beatles were at work trying to get the tracks for Beatles for Sale! recorded and mixed. Busy time for the British. Pomerance's article is an autopsy series of 21 elderly patients with "senile amyloidosis."  At the time, the composition of the fibrils had not been characterized; today we know that most if not all of these cases were likely ATTR (wild type) amyloid.  The report is actually pretty fascinating from a historical standpoint, and it summarizes what was known at the time about systemic amyloidosis citing even older literature. As far as the cases, 3 of 21 patients were reported to have been "sensitive to digitalis" during hospital admissions prior to the terminal ones. No information about digitalis dosing, serum levels, or kidney function was provided. Two of the three patients had had prior myocardial infarctions. 

So, 6 total cases of amyloidosis patients experiencing "digitalis sensitivity." One of the cases provides sufficient detail to justify this diagnosis.  One (pt #2 from the 1961 Cassidy article) almost certainly did not experience digitalis sensitivity but died of hyperkalemia-induced arrhythmia in the setting of pre-existing cardiac tamponade. There is insufficient data on the other four patients (from Pomerance's report, and from the original PubMed search I did) to reach any conclusions one way or the other. 

What about the last part of the cited text from the Falk article? The best support for this was a brief report by Dr A. Rubinow, Martha Skinner, and Alan Cohen from Boston University published in 1981. They describe a laboratory experiment in which they added digoxin to pellets of amyloid fibrils isolated from the spleens of three patients with amyloidosis, and also to samples of ground up tissues: normal human liver, normal human heart, and human heart affected by amyloidosis.  They demonstrated that both pellets of pure amyloid fibrils or heart tissue from a patient with amyloidotic cardiomyopathy bound digoxin, whereas the control tissues (the ones without amyloid) did not. 

Ref: http://circ.ahajournals.org/content/63/6/1285.long

The authors discuss cardiac glycosides' mechanism of action, and - citing the relevance of cardiac tissue levels of the drugs rather than serum levels - postulate that binding of digoxin by amyloid-laden cardiac tissue may increase effective drug levels where it counts. However, they (correctly) point out that it is unknown whether amyloid-bound digoxin retains its pharmacologic activity. Their conclusions? 

"Therapeutic judgement regarding the cautious administration of digoxin in patients with cardiac amyloidosis still rests on clinical grounds."

My conclusions? The same. Patients with amyloid cardiomyopathy are known to be at risk for potentially fatal arrhythmias - its what accounts for the dismal outcomes seen in patients with cardiac stage 3 AL amyloidosis.  It is also clear that patients with structural heart injury from any cause may be at risk for digoxin-induced arrhythmias. So caution is warranted.  A critical review of the literature, however, does not make the case that digoxin can never be used in patients with systemic amyloidosis.  

Successful #Amyloidosis Foundation Benefit: Art, Autos, and Amyloid

Tonight, I attended a fine benefit event which raised funds for the Amyloidosis Foundation. I was joined by two other people from the Karmanos Cancer Institute Myeloma and Amyloidosis team (Silva Pregja and Christy Houde). The event was held at the Inn at St. John's in Plymouth, MI. Here is a picture of the room: 

The Atrium Ballroom at the Inn at St. John's. Image downloaded from the I@SJ's website: http://www.stjohnsgolfconference.com/index.cfm

Very nice night with strolling dinner and a silent auction. Over a hundred people in attendance. The event Co-Chair was the daughter of one of my former patients. I had the opportunity to say a few words at the start of the evening describing the good work the Foundation has been doing for the last decade (educating patients and their physicians about amyloidosis - see link to video of GREAT symposium the Karmanos Cancer Institute and Wayne State University co-sponsored with the Amyloidosis Foundation; funding Junior and Senior level research grants to the tune of three-quarters of a million dollars in total).

Also while there, I had the opportunity to speak with some folks from Millennium, Alnylam, and Prothena - All sponsors of the event, and all in the business of developing amyloidosis therapies (Millennium - Bortezomib, Ixazomib; Alnylam - ALN-TTR02, ALN-TTRsc; Prothena - NEOD001).  

As for the auction, I made a successful run at at a nice piece of art:

Aptly named "Horses" (pardon less-than-professional-quality photo).
A nice little pic for the house and a few bucks for a good cause. 

Patient Page: Why is AL #amyloidosis bad for kidneys?

"Amyloidosis" refers to any one of several diseases in which abnormal protein fibrils accumulate in a person's organs. The most common type is called AL amyloidosis, and the protein fibrils are made up of fragments of antibody proteins called light chains. I posted a slide which illustrates what a light chain is in a previous post ("Why is AL amyloid bad for hearts?"). In AL amyloidosis, the levels of light chains (usually lambda type, but sometimes kappa type) in the blood and urine are elevated.  Light chains are made by plasma cells in the bone marrow, and current AL amyloid therapy targets these plasma cells. 

Any organ's function can be compromised by amyloid deposits.  The kidney is one of the most commonly affected organs, and patients with injured kidneys may have symptoms, including swelling (edema) of the legs, decreased urine output, and lightheadedness due to sudden drops in blood pressure. 

In order to understand how amyloid injures the kidneys, it is helpful to understand how the kidney works. 

A summary of kidney anatomy and function relevant to amyloidosis:

• The kidney is made up of a million microscopic filtration units called nephrons. 
• Each nephron has a filter called the glomerulus, which filters the blood.
• Some parts of the blood, namely water and electrolytes (sodium, potassium, etc), flow through this filter into a tube system where it is processed further. The material that eventually comes out of the end of all this tubing is urine. 
• Other components of the blood, like red blood cells, do not pass through the filter.  
• Although under normal circumstances there is essentially no protein in our urine, it is not because proteins do not pass through the filter. Filtered protein may be reabsorbed (taken back up into the body) in the first part of the tubing system.  The part of the tubing where this takes place is called the proximal tubule.
• The part of the tubing further down the line is called the distal tubule.
• All of these structures, as well as blood vessels within the kidney, are surrounded by tissue which serves as scaffolding to hold it all together. This is the interstitial space, or matrix.  (Its the Jell-O holding all the little pieces of fruit in place in that dessert your mother used to make on Thanksgiving) 

If you want to know more about normal kidney function, see the clear, easy-to-understand post by my friend, nephrologist Joel Topf, in his blog Precious Bodily Fluids.

Light chains can injure the kidneys in a number of ways.  Like albumin, normal light chains are filtered through the glomerulus and then taken back up in the proximal tubule.  The receptors along the lining of the tubule which do this are actually the same for albumin and light chains (cubilin and megalin, if you were wondering).  Problems develop if the light chain levels are abnormally high or if the light chains have an abnormal tendency to form clumps of strands.

• Amyloid light chains, in addition to being filtered, form deposits in the glomerulus itself. This is because these abnormal light chains are taken up by cells within the filter called mesangial cells. Mesangial cells do not take up normal light chains. After the abnormal amyloid light chains are snagged by these cells, they get processed and deposited within the matrix of the filter in strands called fibrils. When a pathologist is looking for amyloid in a kidney biopsy, s/he applies Congo Red stain, which makes these deposits look red under normal light and green under polarized light. As amyloid accumulates in the tissue around the mesangial cells in the glomerulus, the filter is damaged. It becomes "leaky" and the amount of protein lost through the filter increases. 

Kidney biopsy stained with Congo Red stain. Top image is the view under normal light, and the bottom one is the same slide viewed under polarized light.  Everything that turned fluorescent green in the second image is amyloid!
Images snagged from http://www.pathguy.com/lectures/imm-iii.htm

• Increased protein delivery to the proximal tubule is bad for one's kidneys. The receptors to reabsorb albumin and light chains can become overwhelmed. Excess albumin is lost in the urine, and it can make the urine appear "foamy."  Very low blood albumin levels are what cause the swelling (edema) and low blood pressure (hypotension) amyloidosis patients experience. Even though I.V. albumin solutions exist, it is not feasible to replace it because infused albumin suffers the same fate as the patient's "home-grown" albumin: flushed. Excess light chains can also cause problems, as they can bind to other proteins in the urine and form casts (clumps that clog up the distal tubule, which in turn causes problems upstream). Cast formation is the leading cause of kidney injury in multiple myeloma, but less of an issue in amyloidosis.  I posted about cast nephropathy previously (check that out). 
• Inflammation plays a role in amyloid kidney injury. Abnormal light chains, when taken up by the cells in the proximal tubule actually injure the cells in that part of the kidney. Excess albumin in the tubular system and abnormal amyloid light chains in the cells lining the tubular system trigger inflammation and eventually scarring of the interstitial area. This is why AL amyloidosis patient with persisting heavy albuminuria (albumin in the urine) due to filter damage may have continued worsening of their renal function even after the amyloidosis has been treated and the light chain levels are no longer elevated: albumin-mediated kidney injury. In my own practice, this is a common and frustrating problem. One glimmer of hope: it is possible that one of the treatments commonly used in the treatment of AL amyloidosis - the proteasome inhibitor bortezomib (Velcade) - targets this inflammatory pathway.  Other drugs in this same family (carfilzomib (Kyprolis) and ixazomib (MLN-9708)) are currently undergoing testing as therapy for AL amyloidosis. These drugs may not only kill bad-acting plasma cells, but also help the kidney dodge some albumin-mediated damage. Friend and colleague Meletios Dimopoulos has published extensively on this topic; check out this article describing the improvement in kidney function seen in myeloma patients who received bortezomib therapy. 

Kidney transplant has been undertaken in a limited number of patients with myeloma and/or amyloidosis. A major concern is that the same disease-related processes which caused the original kidneys to fail will recur in a transplanted kidney. Also, the fact that patients with these diseases often have limited survival independent of kidney function begs the question of whether precious  donor kidneys are best used in this situation. With newer therapies leading to higher remission rates and longer survival in both myeloma and AL amyloidosis, the idea that it may be time to revisit the conventional wisdom about organ transplantation is gaining traction (like here).

Lets call it a wrap. While I call this a "Patient Page," I used a lot of medical terminology. I tried to define everything in common language. Even so, it is probably clear I expect a lot from my readers. If there is anything in this page which requires clarification, TELL ME. Email me, or post it as a comment. I want the content of this (and every) post to be as clear and helpful as possible.