A 51-Year-Old Man With Congestive Heart Failure and Renal Abnormalities

Correct Answer: B. The presence and degree of cardiac involvement.

Discussion. Health care providers may recall the “clinical pathology conference”, a training staple wherein a senior staff member is given a mysterious case study and asked to generate differential diagnoses and ultimately, a final diagnosis.

One of the more frequent presentations during these conferences are patients with multisystem illnesses affecting different organs all over the patient’s body, any one of which might have a mundane and easy explanation. But the harder explanation is determining why these illnesses are occurring in concert to the same patient at the same time. Often, the diagnosis turns out to be amyloidosis, which is precisely the situation in this case.

The prognosis of amyloidosis is slowly improving. In 1999, patients with amyloidosis and overt chronic heart failure (CHF) survived 4 months to 6 months and those without CHF survived a median of 30 months.¹ Today, the early mortality of patients with CHF remains high: 30% to 45% at 6 months to 12 months. But patients without CHF, eg, nephrotic presentations, have survivorship measured in years using new therapy protocols.² A variety of clinical and laboratory markers have been shown to be prognostic. These include the presence of CHF perse and a schema for following CHF using detailed cardiac ultrasounds, troponin levels, and NT-proBNP (natriuretic protein). Of course, the worse the ejection fraction (EF), interventricular wall thickness, and cardiac protein leakage, the more ominous the prognosis. Therefore, answer B is correct with CHF dominating prognosis risk. Renal function, presence or degree of nephrotic syndrome and even age are not as powerful prognostic indicators as degree of cardiac involvement.

Several other studies are also accurate markers for all patients with amyloidosis and include serum free light chains (FLC) titres and bone marrow plasma cell percentages (< 10% = good; > 20% = poor).² Both of these are also used to easily follow response to therapy or progression. Tissue recovery meanwhile is a later finding even in responsive patients, with first responses in impacted organs being roughly 9, 6, and 6 months for heart, kidney, and liver, respectively.²

Pathophysiology. The catalyst in the pathophysiology of amyloid formation is essentially a biochemical event. A small (by multiple myeloma comparisons) cluster of plasma cells make an ongoing amount of abnormal, monoclonal immunoglobulin protein, which is generally composed of light chains and/or light chain fragment in amylogenic light chain amyloidosis, the most common variety by far. There are other variations containing heavy chains or nonlight chain substances, but these compromise less than 10% of cases. The aforementioned amylogenic light chains have the unfortunate immunohistochemical capability of polymerizing into amyloid sheets and fibrils. This is the substance that is the classical Congo Red staining diagnostic for amyloidosis. This material is non-degradable by the body (or at least very slowly so). Deposits into tissues cause both space and biological disruption (such as apoptosis induction in infiltrated cardiac tissue) with eventual organ dysfunction, failure and symptoms.¹ Please note that the “order” or timeline evolution is monoclonal light chain m-protein; accumulation of this material with amyloid sheets and fibrils forming in target tissues and organs; tissue/organ disease and symptomology. When therapy is effective, any improvement takes the same pathway such that hematological response/improvement precedes with lowering or obliteration of the plasma cell clone and m-protein first. Then, symptom regression follows and finally removal of amyloid on imaging is seen.

Presentation. Although quite systemic, the predominant obvious organ targets clinically are heart, kidney, liver, and peripheral neuropathy. Heart and/or kidney will be in the presentation of 60% to 80% of cases.² Cardiac cases will present with peripheral edema and symptoms of CHF due to cardiomyopathy. The usual suspects of coronary artery disease or prolonged hypertension will be absent and “unexplained CHF” or “diastolic dysfunction” CHF should trigger questioning regarding whether amyloidosis is the cause.¹ Other signs include the presence of thickened interventricular septum, diffuse heart wall thickness with no valvular lesions, and the legendary “glistening” on cardiac scan.² Renal presentation is almost always proteinuria. In fact, nephrotic syndrome levels, in the absence of known cause such as diabetes mellitus or hypertension. Nephrotic syndrome is so clinically obvious that it is the most common early syndrome of amyloid disease.¹ Liver involvement with hepatomegaly and increased alkaline phosphatase (again, without obvious cause) and distal polyneuropathy are also seen in presentations but are less common (glossomegaly and periorbital purpura even less so [< 10%]).^1,2

An important backdoor presentation that is more commonly seen today due to increased blood testing, is a small, low titre light chain monoclonal gammopathies of undetermined significance (MGUS) or either serum or urine immunofixation. Around 90% of patients with amyloidosis will have monoclonal light chains on serum and/or urine.^1,2 Beside classical myeloma evaluation, such patients should be more closely followed than the level of the m-protein would suggest because their illness may blossom into amyloidosis more so than a myeloma picture.

Unexplained CHF, especially cardiomyopathy type, nephrotic syndrome, infiltrative liver disease, or peripheral/autonomic neuropathy without obvious other causation should trigger an evaluation for amyloidosis. Similarly, a “light chain MGUS” usually of low titre should also raise a caution flag in a patient’s follow-up. When more than one target organ system is involved simultaneously, a real red flag should be raised and amyloid work up initiated. Such is the situation in our current case–CHF (diastolic dysfunction) and nephrotic syndrome without obvious cause in the same patient.

Diagnosis and evaluation. There is no specific blood test or abnormal blood value available at this time to confirm the diagnosis of amyloid. And although suggestive, no imaging studies can do so either. A biopsy demonstrating the presence of amyloid deposits in tissue is required. Two relatively easy areas of access to sample are the subcutaneous fat pad and bone marrow biopsy. When combined, a 90% yield of cases is attained.²

Renal biopsy is another quite common procedure since it is a part of a nephrotic workup. The time tested stain, even today, is the Congo Red stain demonstrating green birefringence, which reflects the fibril biochemistry of amyloid deposits.² For our purposes, amyloidosis is by far the amylogenic light chain amyloid type with the precursor protein monoclonal light chains.

Although the therapeutics for amyloidosis are complex, the order of battle is to attack the hematology lesion. This can be done by lowering or obliterateing the plasma cell clone and thus reducing the level of the FLC precursor proteins. A variety of chemotherapeutic agents can do this and there is similarity to multiple myeloma protocols. Daratunumab, cyclophosphamide, bortezimib, and dexamethasone is the current keystone therapy capable of producing a very high rate of response.^3,4 In selected cases with very good responses, therapy has been topped off with autologous bone marrow transplant and attained complete responses (eg, obliteration of the monoclonal plasma cell clone and free light chains) in 70% and 5-year survival rates of 90%.^2,4

Patient follow-up. The combined and simultaneous appearance of diastolic CHF and nephrotic syndrome triggered an amyloid evaluation. Blood studies revealed a low titre monoclonal protein of 0.4 gm/L which was lambda light chains and a bone marrow showed 8% plasma cells with lambda light chain restriction. Both fat pad and bone marrow biopsy were positive for amyloid. Troponin I was 0.12 ng/mL and NT-proBNP was 2460 pg/L.

The patient was referred to a specialty center and received a total of 6 months treatment with the ddaratunumab – CyBorD regimen and has achieved a complete hematologic response with obliteration of both the plasma cell clone and free light chains in the serum. Cardiac biomarkers have improved to normal and his nephrotic syndrome has resolved with normal renal function. Echocardiographic abnormalities have not yet changed, but EF has improved to 56%. He is currently being evaluated for autologous stem cell transplantation.

What’s The Take Home? The last two decades have indeed altered the entire scenario of amyloidosis. The job of the general practitioner and internist is to suspect the diagnosis when confronted with a patient with a variety (but especially cardiac and renal) syndromes of obscure origin; confirm the unifying diagnosis with fat pad/bone marrow biopsy; and begin an evaluation process with appropriate imaging and blood studies. Once there, specialists can deliver and oversee therapy, which is transforming a once uniformly fatal disease.^5,6

AFFILIATIONS:
¹Lewis Katz School of Medicine at Temple University, Philadelphia, PA
²Department of Medicine, Temple University Hospital, Philadelphia, PA

CITATION:
Rubin RN. A 51-year-old man with congestive heart failure and renal abnormalities. Consultant. 2023;63(7):e8. doi:10.25270/con.2023.06.000006.

DISCLOSURES:
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)